A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of
drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhal ...
that acts as a combined
reuptake inhibitor
Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transmitt ...
of the
monoamine
Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.
All monoamines ar ...
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neur ...
s
serotonin,
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...
, and
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...
. It does this by
concomitantly inhibiting the
serotonin transporter
The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein th ...
(SERT),
norepinephrine transporter (NET), and
dopamine transporter (DAT), respectively. Inhibition of the
reuptake
Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of trans ...
of these neurotransmitters increases their
extracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
concentration
In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', '' number concentration'' ...
s and, therefore, results in an increase in
serotonergic
Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chem ...
,
adrenergic
Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine ...
, and
dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate do ...
neurotransmission
Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...
.
SNDRIs were developed as potential
antidepressant
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness ...
s and treatments for other disorders, such as
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
,
cocaine addiction
Cocaine dependence is a neurological disorder that is characterized by withdrawal symptoms upon cessation from cocaine use. It also often coincides with cocaine addiction which is a biopsychosocial disorder characterized by persistent use o ...
,
attention-deficit hyperactivity disorder (ADHD), and
chronic pain
Chronic pain is classified as pain that lasts longer than three to six months. In medicine, the distinction between acute and chronic pain is sometimes determined by the amount of time since onset. Two commonly used markers are pain that continues ...
. They are an extension of
selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.
SSRIs increase the extracellul ...
s (SSRIs) and
serotonin-norepinephrine reuptake inhibitors (SNRIs) whereby the addition of dopaminergic action is thought to have the possibility of heightening therapeutic benefit. However, increased
side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s and
abuse potential are potential concerns of these agents relative to their SSRI and SNRI counterparts.
The SNDRIs are similar to non-selective
monoamine oxidase inhibitor
Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, esp ...
s (MAOIs) such as
phenelzine and
tranylcypromine
Tranylcypromine, sold under the brand name Parnate among others,Drugs.co Page accessed April 17, 2016 is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme mono ...
in that they increase the action of all three of the major monoamine neurotransmitters. They are also similar to
serotonin–norepinephrine–dopamine releasing agents (SNDRAs) like
MDMA
3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for recreational purposes. The desired ...
("ecstasy") and
α-ethyltryptamine (αET) for the same reason, although they act via a different
mechanism and have differing physiological and qualitative effects.
Although their primary mechanisms of action are as
NMDA receptor antagonist
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induc ...
s,
ketamine
Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ...
and
phencyclidine
Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted percepti ...
are also SNDRIs and are similarly encountered as drugs of abuse.
Indications
Depression
Major depressive disorder
Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
(MDD) is the foremost reason supporting the need for development of an SNDRI.
According to the
World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...
,
depression is the leading cause of
disability
Disability is the experience of any condition that makes it more difficult for a person to do certain activities or have equitable access within a given society. Disabilities may be cognitive, developmental, intellectual, mental, physical, s ...
and the 4th leading contributor to the
global burden of disease in 2000. By the year 2020, depression is projected to reach 2nd place in the ranking of
DALYs.
About 16% of the population is estimated to be affected by major depression, and another 1% is affected by bipolar disorder, one or more times throughout an individual's lifetime. The presence of the common symptoms of these disorders are collectively called 'depressive syndrome' and includes a long-lasting
depressed mood, feelings of guilt, anxiety, and recurrent thoughts of death and suicide.
Other symptoms including poor concentration, a disturbance of sleep rhythms (
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy ...
or
hypersomnia
Hypersomnia is a neurological disorder of excessive time spent sleeping or excessive sleepiness. It can have many possible causes (such as seasonal affective disorder) and can cause distress and problems with functioning. In the fifth edition o ...
), and severe fatigue may also occur. Individual patients present differing subsets of symptoms, which may change over the course of the disease highlighting its multifaceted and heterogeneous nature.
[ Depression is often highly comorbid with other diseases, e.g. ]cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, ...
(myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ...
, stroke),[ ]diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
, cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
, Depressed subjects are prone to smoking, substance abuse, eating disorders
An eating disorder is a mental disorder defined by abnormal eating behaviors that negatively affect a person's physical or mental health. Only one eating disorder can be diagnosed at a given time. Types of eating disorders include binge eating ...
, obesity, high blood pressure, pathological gambling and internet addiction, and on average have a 15 to 30 year shorter lifetime compared with the general population.
Major depression can strike at virtually any time of life as a function of genetic and developmental pre-disposition in interaction with adverse life-events. Although common in the elderly, over the course of the last century, the average age for a first episode has fallen to ~30 years. However, depressive states (with subtly different characteristics) are now frequently identified in adolescents and even children. The differential diagnosis (and management) of depression in young populations requires considerable care and experience; for example, apparent depression in teenagers may later transpire to represent a prodromal phase of schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...
.[
The ability to work, familial relationships, social integration, and self-care are all severely disrupted.][
The genetic contribution has been estimated as 40-50%. However, combinations of multiple genetic factors may be involved because a defect in a single gene usually fails to induce the multifaceted symptoms of depression.][
]
Pharmacotherapy
There remains a need for more efficacious antidepressant agents. Although two-thirds of patients will ultimately respond to antidepressant treatment, one-third of patients respond to placebo, and remission is frequently sub-maximal (''residual'' symptoms). In addition to post-treatment relapse, depressive symptoms can even recur in the course of long-term therapy ('' tachyphylaxis''). Also, currently available antidepressants all elicit undesirable side-effects, and new agents should be divested of the distressing side-effects of both first and second-generation antidepressants.[
Another serious drawback of all antidepressants is the requirement for long-term administration prior to maximal therapeutic efficacy. Although some patients show a partial response within 1–2 weeks, in general one must reckon with a delay of 3–6 weeks before full efficacy is attained. In general, this delay to onset of action is attributed to a spectrum of long-term adaptive changes. These include receptor desensitization, alterations in intracellular transduction cascades and ]gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. ...
, the induction of neurogenesis
Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs ...
, and modifications in synaptic architecture and signaling.[
Depression has been associated with impaired ]neurotransmission
Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...
of serotonergic
Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chem ...
(5-HT), noradrenergic (NE), and dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate do ...
(DA) pathways, although most pharmacologic treatment strategies directly enhance only 5-HT and NE neurotransmission.[ In some patients with depression, DA-related disturbances improve upon treatment with antidepressants, it is presumed by acting on serotonergic or noradrenergic circuits, which then affect DA function. However, most antidepressant treatments do not ''directly'' enhance DA neurotransmission, which may contribute to residual symptoms, including impaired ]motivation
Motivation is the reason for which humans and other animals initiate, continue, or terminate a behavior at a given time. Motivational states are commonly understood as forces acting within the agent that create a disposition to engage in goal-dire ...
, concentration
In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', '' number concentration'' ...
, and pleasure
Pleasure refers to experience that feels good, that involves the enjoyment of something. It contrasts with pain or suffering, which are forms of feeling bad. It is closely related to value, desire and action: humans and other conscious anima ...
.
Preclinical and clinical research
Clinical research is a branch of healthcare science that determines the safety and effectiveness ( efficacy) of medications, devices, diagnostic products and treatment regimens intended for human use. These may be used for prevention, treat ...
indicates that drugs inhibiting the reuptake of all three of these neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neur ...
s can produce a more rapid onset of action and greater efficacy than traditional antidepressants.[
DA may promote ]neurotrophic
Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their tro ...
processes in the adult hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
, as 5-HT and NA do. It is thus possible that the stimulation of multiple signalling pathways resulting from the elevation of all three monoamines may account, in part, for an accelerated and/or greater antidepressant response.[
Dense connections exist between monoaminergic neurons. Dopaminergic neurotransmission regulates the activity of 5-HT and NE in the dorsal raphe nucleus (DR) and ]locus coeruleus
The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system.
The locus coer ...
(LC), respectively. In turn, the ventral tegmental area
The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is th ...
(VTA) is sensitive to 5-HT and NE release.[
In the case of SSRIs, the promiscuity among transporters means that there may be more than a single type of neurotransmitter to consider (e.g. 5-HT, DA, NE, etc.) as mediating the therapeutic actions of a given medication. MATs are able to transport monoamines other than their "native" neurotransmitter. It was advised to consider the role of the ]organic cation transporter An organic cation transport protein mediates the transport of organic cations across the cell membrane. These proteins are members of the solute carrier family, subfamily 22. This family of proteins can also transport zwitterions and anions, thou ...
s (OCT) and the plasma membrane monoamine transporter (PMAT).
To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout
A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, a ...
(KO) mice and wild-type
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
littermates were studied in the forced swim test
The behavioural despair test (or Porsolt forced swimming test) is a test, centered on a rodent's response to the threat of drowning, whose result has been interpreted as measuring susceptibility to negative mood. It is commonly used to measure the ...
(FST), the tail suspension test, and for sucrose consumption. The effects of DAT KO in animal models of depression
Animal models of depression are research tools used to investigate depression and action of antidepressants as a simulation to investigate the symptomatology and pathophysiology of depressive illness or used to screen novel antidepressants.
In ...
are larger than those produced by NET or SERT KO, and unlikely to be simply the result of the confounding effects of locomotor hyperactivity; thus, these data support reevaluation of the role that DAT expression could play in depression and the potential antidepressant effects of DAT blockade.[
The SSRIs were intended to be highly selective at binding to their molecular targets. However it may be an oversimplification, or at least controversial in thinking that complex ]psychiatric
Psychiatry is the medical specialty devoted to the diagnosis, prevention, and treatment of mental disorders. These include various maladaptations related to mood, behaviour, cognition, and perceptions. See glossary of psychiatry.
Initial psyc ...
(and neurological) diseases are easily solved by such a monotherapy. While it may be inferred that dysfunction of 5-HT circuits is likely to be a part of the problem, it is only one of many such neurotransmitters whose signaling can be affected by suitably designed medicines attempting to alter the course of the disease
A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
state.
Most common CNS disorders are highly polygenic
A polygene is a member of a group of non- epistatic genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance (polygenic inheritance, multigenic inheritance, quantitative inheritance), a type o ...
in nature; that is, they are controlled by complex interactions between numerous gene products. As such, these conditions do not exhibit the single gene defect basis that is so attractive for the development of highly-specific drugs largely free of major undesirable side-effects ("the magic bullet
Magic bullet may refer to:
* Enchanted bullet obtained through a contract with the devil in the German folk legend Freischütz
** ''Der Freischütz'', an opera by Carl Maria von Weber based on the legend
* Magic bullet (medicine), the pharmacologi ...
"). Second, the exact nature of the interactions that occur between the numerous gene products typically involved in CNS disorders remain elusive, and the biological mechanisms underlying mental illnesses are poorly understood.
Clozapine
Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate resp ...
is an example of a drug used in the treatment of certain CNS disorders, such as schizophrenia, that has superior efficacy precisely because of its broad-spectrum mode of action. Likewise, in cancer chemotherapeutics, it has been recognized that drugs active at more than one target have a higher probability of being efficacious.
In addition, the nonselective MAOIs and the TCA SNRIs are widely believed to have an efficacy that is superior to the SSRIs normally picked as the first-line choice of agents for/in the treatment of MDD and related disorders. The reason for this is based on the fact that SSRIs are safer than nonselective MAOIs and TCAs. This is both in terms of there being less mortality in the event of overdose, but also less risk in terms of dietary restrictions (in the case of the nonselective MAOIs), hepatotoxicity (MAOIs) or cardiotoxicity (TCAs).
Applications other than depression
* Alcoholism
Alcoholism is, broadly, any drinking of alcohol that results in significant mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognized diagnostic entity. Predomina ...
(c.f. DOV 102,677)
* Cocaine addiction
Cocaine dependence is a neurological disorder that is characterized by withdrawal symptoms upon cessation from cocaine use. It also often coincides with cocaine addiction which is a biopsychosocial disorder characterized by persistent use o ...
(e.g., indatraline)
* Obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
(e.g., amitifadine
Amitifadine (developmental code names DOV-21,947, EB-1010) is a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) or so-called triple reuptake inhibitor (TRI) which is or was being developed by Euthymics Bioscience It was under de ...
, tesofensine
Tesofensine (NS2330) is a serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity. Tesofensine was originally developed by a Danish biotechnology compa ...
)
* Attention-deficit hyperactivity disorder (ADHD) (c.f. NS-2359
NS-2359 (GSK-372,475) is a serotonin-norepinephrine-dopamine reuptake inhibitor. It was under development by GlaxoSmithKline (GSK) as an antidepressant, but was discontinued in 2009 when phase II clinical trials showed the drug was not effectiv ...
, EB-1020)
* Chronic pain
Chronic pain is classified as pain that lasts longer than three to six months. In medicine, the distinction between acute and chronic pain is sometimes determined by the amount of time since onset. Two commonly used markers are pain that continues ...
(c.f. bicifadine
Bicifadine (DOV-220,075) is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) discovered at American Cyanamid as an analgesic drug candidate, and licensed to DOV Pharmaceutical in 1998 after American Cyanamid was acquired by Wyeth.
...
)
* Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
List of SNDRIs
Approved pharmaceuticals
* Mazindol (Mazanor, Sanorex) – anorectic
An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic.
The term is (from the Greek ''ἀν-'' (an-) = "without" ...
; 50 nM for SERT, 18 nM for NET, 45 nM for DAT
* Nefazodone
Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued. BMS withdrew it fro ...
(Serzone, Nefadar, Dutonin) – antidepressant
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness ...
; non-selective; 200 nM at SERT, 360 nM at NET, 360 nM at DAT
Sibutramine (Meridia) is a withdrawn anorectic that is an SNDRI ''in vitro'' with values of 298 nM at SERT, 5451 at NET, 943 nM at DAT. However, it appears to act as a prodrug ''in vivo'' to metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...
s that are considerably more potent and possess different ratios of monoamine reuptake inhibition A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine ...
in comparison, and in accordance, sibutramine behaves contrarily as an SNRI (73% and 54% for norepinephrine and serotonin reuptake inhibition, respectively) in human volunteers with only very weak and probably inconsequential inhibition of dopamine reuptake (16%).
Venlafaxine
Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic di ...
(Effexor) is sometimes referred to as an SNDRI, but is extremely imbalanced with values of 82 nM for SERT, 2480 nM for NET, and 7647 nM for DAT, with a ratio of 1:30:93. It may weakly inhibit the reuptake of dopamine at high doses.
Coincidental
* Esketamine (Ketanest S) – anesthetic
An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia — in other words, to result in a temporary loss of sensation or awareness. They may be divided into tw ...
; ''S''-enantiomer
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
of ketamine; weak SNDRI action likely contributes to effects and abuse potential
* Ketamine
Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ...
(Ketalar) – anesthetic and dissociative
Dissociatives, colloquially dissos, are a subclass of hallucinogens which distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of ...
drug of abuse; weak SNDRI action likely contributes to effects and abuse potential
* Phencyclidine
Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted percepti ...
(Sernyl) – discontinued anesthetic and dissociative psychostimulant
Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
drug of abuse; SNDRI action likely contributes to effects and abuse potential
* Tripelennamine (Pyribenzamine) – antihistamine
Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provide ...
; weak SNDRI; sometimes abused for this reason
* Mepiprazole
Undergoing clinical trials
* Ansofaxine (LY03005/LPM570065). Completed Phase 2 & 3 trials. FDA accepted NDA application.
* Centanafadine (EB-1020) �
see here for details
1 to 6 to 14 ratio for NDS. Completed Phase 3 trials for ADHD.
* OPC-64005 - In phase 2 trials (2022)
* Lu AA37096 �
see here
(SNDRI and 5-HT6 modulator)
* NS-2360 – principle metabolite of tesofensine
* Tesofensine
Tesofensine (NS2330) is a serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity. Tesofensine was originally developed by a Danish biotechnology compa ...
(NS-2330) (2001) In trials for obesity.
Failed clinical trials
* Bicifadine
Bicifadine (DOV-220,075) is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) discovered at American Cyanamid as an analgesic drug candidate, and licensed to DOV Pharmaceutical in 1998 after American Cyanamid was acquired by Wyeth.
...
(DOV-220,075) (1981)
* BMS-866,949
* Brasofensine (NS-2214, BMS-204,756) (1995)
* Diclofensine (Ro 8–4650) (1982)
* DOV-216,303
DOV 216,303 is an experimental antidepressant drug originally developed by DOV Pharmaceutical and was licensed to Merck & Co. in 2004; Merck and DOV terminated their relationship in December 2006.
It is a triple reuptake inhibitor (TRI), or ...
(2004)
* EXP-561
EXP-561 is an investigational drug that acts as an inhibitor of the reuptake of serotonin, dopamine, and norepinephrine. It was developed in the 1960s by Du Pont and was suggested as a potential antidepressant
Antidepressants are a class of ...
(1965)
* Liafensine (BMS-820,836)
* NS-2359
NS-2359 (GSK-372,475) is a serotonin-norepinephrine-dopamine reuptake inhibitor. It was under development by GlaxoSmithKline (GSK) as an antidepressant, but was discontinued in 2009 when phase II clinical trials showed the drug was not effectiv ...
(GSK-372,475)
* RG-7166 (2009–2012)
* SEP-227,162
* SEP-228,425
* SEP-228,432
* Amitifadine
Amitifadine (developmental code names DOV-21,947, EB-1010) is a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) or so-called triple reuptake inhibitor (TRI) which is or was being developed by Euthymics Bioscience It was under de ...
(DOV-21,947, EB-1010) (2003)
* Dasotraline
Dasotraline (INN; former developmental code name SEP-225,289) is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) that was under development by Sunovion for the treatment of attention-deficit hyperactivity disorder (ADHD) and bing ...
(SEP-225,289)
* Lu AA34893 �
see here
(SNDRI and 5-HT2A, α1, and 5-HT6 modulator)
* Tedatioxetine (Lu AA24530) – SNDRI and 5-HT2C, 5-HT3, 5-HT2A, and α1 modulator
Designer drugs
A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. Des ...
* 3-Methyl-PCPy
3-Methyl-PCPy (3-Me-PCPy) is an arylcyclohexylamine derivative with an unusual spectrum of pharmacological effects, acting as both a potent NMDA antagonist and also a triple reuptake inhibitor which inhibits reuptake of all three monoamine neur ...
* Naphyrone (O-2482, naphthylpyrovalerone, NRG-1) (2006)
Research compounds (no record of having been taken by humans)
* 3,3-Diphenylcyclobutanamine
3,3,-Diphenylcyclobutanamine is a psychostimulant drug which was originally prepared as an antidepressant in the late 1970s. It appears to inhibit the reuptake of serotonin, norepinephrine, and dopamine, and may also induce their release as wel ...
(1978)
* 3,4-Dichlorotametraline (''trans''-(1R,4S)-sertraline
Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differ ...
) (1980)
* D-161 (2008)
* Desmethylsertraline
Desmethylsertraline (DMS), also known as norsertraline, is an active metabolite of the antidepressant drug sertraline. Like sertraline, desmethylsertraline acts as a monoamine reuptake inhibitor, and may be responsible for some of its parent's t ...
– active metabolite An active metabolite is an active form of a drug after it has been processed by the body.
Metabolites of drugs
An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...
of sertraline; 76 nM for SERT, 420 nM for NET, 440 nM for DAT
* DMNPC (2000)
* DOV-102,677
DOV-102,677 is a psychoactive drug being developed by Merck and is currently in clinical trials. It is a triple reuptake inhibitor (TRI), or serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It is the (−)-enantiomer of DOV-216,3 ...
(2006–2011)
* Fezolamine (Win-41,528-2)
* GSK1360707F
GSK1360707F is a potent and selective SNDRI, triple reuptake inhibitor. It is chemically related to amitifadine and NS-2359 (GSK-372,475). Until recently, it was under development for the treatment of major depressive disorder; its development ...
(2010)
* HP-505
* Indatraline (1985)
* JNJ-7925476
JNJ-7925476 is a triple reuptake inhibitor antidepressant discovered by Johnson & Johnson, but never marketed.
These molecules were first prepared by Bruce E. Maryanoff and coworkers during the late 1970s–1980s. The structure is a pyrrol ...
(2008; first appeared in 1987)
* JZ-IV-10
JZ-IV-10 is a piperidine derivative related to cocaine which acts as a highly potent serotonin–norepinephrine–dopamine reuptake inhibitor (also called SNDRI, or triple reuptake inhibitor). The eugeroic modafinil
Modafinil, sold unde ...
(2005)
* JZAD-IV-22 (2010)
* LR-5182
LR-5182 is a stimulant drug which acts as a norepinephrine–dopamine reuptake inhibitor, structurally related to the better known drug fencamfamine. It was developed by the pharmaceutical company Eli Lilly in the 1970s, and researched for poten ...
(1978)
* Methylnaphthidate
HDMP-28 or methylnaphthidate is a piperidine based stimulant drug, closely related to methylphenidate, but with the benzene ring replaced by naphthalene. It is a potent dopamine reuptake inhibitor, with several times the potency of methylphen ...
(HDMP-28) (2001)
* MI-4
* PRC200-SS
PRC200-SS is an experimental drug of the triple reuptake inhibitor class that was investigated by the Mayo Clinic.
Preclinical toxicology studies of PRC200-SS in cynomolgus monkeys showed dose proportional kidney toxicity, precluding any furthe ...
(2008), PRC050, and PRC025
China, officially the People's Republic of China (PRC), is a country in East Asia. It is the world's most populous country, with a population exceeding 1.4 billion, slightly ahead of India. China spans the equivalent of five time zones ...
* SKF-83,959 (2013)
* TP1 (2011)
* Various phenyltropane
Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, ...
s, such as WF-23, dichloropane, and RTI-55
RTI(-''4229'')-55, also called RTI-55 or iometopane, is a phenyltropane-based psychostimulant used in scientific research and in some medical applications. This drug was first cited in 1991. RTI-55 is a non-selective dopamine reuptake inhibitor d ...
* NS9775
Herbals
* The coca flour contains cocaine
Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...
– natural alkaloid
Alkaloids are a class of basic
BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Th ...
and drug of abuse
* ''Ginkgo biloba
''Ginkgo biloba'', commonly known as ginkgo or gingko ( ), also known as the maidenhair tree, is a species of tree native to China. It is the last living species in the order Ginkgoales, which first appeared over 290 million years ago. Fossils ...
'' extract (EGb761) – "The norepinephrine (NET), the serotonin (SERT), the dopamine (DAT) uptake transporters and MAO activity are inhibited by EGb761 in vitro"
* St John's Wort
''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus '' Hypericum''.
Possibly a hybrid between '' H. maculatum'' and '' H. attenuatum'', the species can be found ...
– natural product and over-the-counter herbal antidepressant
** Hyperforin
** Adhyperforin
Adhyperforin is a phytochemical found in the members of the plant genus ''Hypericum'' including St. John's Wort. It has a very similar pharmacological profile to hyperforin and acts as a TRPC6 ion channel activator, thereby inhibiting the reuptak ...
** Uliginosin B – IC50 DA = 90 nM, 5-HT = 252 nM, NE = 280 nM
*Oregano
Oregano (, ; ''Origanum vulgare'') is a species of flowering plant in the mint family Lamiaceae. It was native to the Mediterranean region, but widely naturalised elsewhere in the temperate Northern Hemisphere.
Oregano is a woody perennial pla ...
extract.
*Although not specifically a SNDRI, '' Rosmarinus officinalis'' is one of the trimonoamine modulator (TMM) that affect SER/CAs.
* Hederagenin:
Toxicological
Toxicological screening is important to ensure safety of the drug molecules. In this regard, the p m-dichloro
Chlorine is a chemical element with the symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate between them. Chlorine is ...
phenyl
In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydroge ...
analog
Analog or analogue may refer to:
Computing and electronics
* Analog signal, in which information is encoded in a continuous variable
** Analog device, an apparatus that operates on analog signals
*** Analog electronics, circuits which use analo ...
of venlafaxine
Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic di ...
was dropped from further development after its potential
Potential generally refers to a currently unrealized ability. The term is used in a wide variety of fields, from physics to the social sciences to indicate things that are in a state where they are able to change in ways ranging from the simple r ...
mutagenicity was called into question
A question is an utterance which serves as a request for information. Questions are sometimes distinguished from interrogatives, which are the grammatical forms typically used to express them. Rhetorical questions, for instance, are interrogat ...
. The mutagenicity of this compound is still doubtful though. It was dropped for other reasons likely related to speed
In everyday use and in kinematics, the speed (commonly referred to as ''v'') of an object is the magnitude of the change of its position over time or the magnitude of the change of its position per unit of time; it is thus a scalar quantity ...
at which it could be released onto the market relative to the more developed compound venlafaxine
Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic di ...
. More recently, the carcinogenicity of PRC200-SS
PRC200-SS is an experimental drug of the triple reuptake inhibitor class that was investigated by the Mayo Clinic.
Preclinical toxicology studies of PRC200-SS in cynomolgus monkeys showed dose proportional kidney toxicity, precluding any furthe ...
was likewise reported
Dive is a Belgian electronic dance music project formed in 1990 by Dirk Ivens (Absolute Body Control, Klinik, Blok 57, Sonar). Dive's "audio trademark" is the experimental sound of abused drum machines, pulsating through crackling distortion ...
.
(+)-CPCA ("nocaine
(+)-CPCA (nocaine, 3α-carbomethoxy-4β-(4-chlorophenyl)-''N''-methylpiperidine aka CTDP 31,446
) is a stimulant drug similar in structure to pethidine (an opioid that possesses NDRI actions) and to RTI-31, but nocaine is lacking the two-carbo ...
") is the 3''R'',4''S'' piperidine
Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic compound, heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless ...
stereoisomer
In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms i ...
of (phenyltropane
Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, ...
based) RTI-31
(–)-2β-Carbomethoxy-3β-(4'-chlorophenyl)tropane (RTI-''4229''-31) is a synthetic structural analog, analog of cocaine that acts as a stimulant. Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. A ...
. It is non addictive, although this might be due to it being a NDRI, not a SNDRI. The β-naphthyl analog of "Nocaine"[ is a SNDRI though in the case of both the ''SS'' and ''RR'' enantiomers. Consider the piperidine analogs of brasofensine][ and ]tesofensine
Tesofensine (NS2330) is a serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity. Tesofensine was originally developed by a Danish biotechnology compa ...
. These were prepared by NeuroSearch (In Denmark
)
, song = ( en, "King Christian stood by the lofty mast")
, song_type = National and royal anthem
, image_map = EU-Denmark.svg
, map_caption =
, subdivision_type = Sovereign state
, subdivision_name = Kingdom of Denmark
, establishe ...
) by the chemists Peter Moldt (2002), and Frank Wätjen (2004–2009). There are four separate isomers to consider (''SS'', ''RR'', ''S/R'' and ''R/S''). This is because there are two chiral carbon sites of asymmetry
Asymmetry is the absence of, or a violation of, symmetry (the property of an object being invariant to a transformation, such as reflection). Symmetry is an important property of both physical and abstract systems and it may be displayed in pre ...
(means 2 to the power of n isomers to consider where n is the number of chiral carbons). They are therefore a diastereo(iso)meric pair of racemers. With a racemic
In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
pair of diastereomers, there is still the question of syn ( cis) or anti
Anti may refer to:
*Anti-, a prefix meaning "against"
*Änti, or Antaeus, a half-giant in Greek and Berber mythology
*A false reading of '' Nemty'', the name of the ferryman who carried Isis to Set's island in Egyptian mythology
*Áńt’į, or ...
(trans
Trans- is a Latin prefix meaning "across", "beyond", or "on the other side of".
Used alone, trans may refer to:
Arts, entertainment, and media
* Trans (festival), a former festival in Belfast, Northern Ireland, United Kingdom
* ''Trans'' (fil ...
). In the case of the phenyltropanes, although there are four chiral carbons, there are only eight possible isomers to consider. This is based on the fact that the compound is bicyclic and therefore does not adhere to the equation given above.
It is complicated to explain which isomers
In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers.
...
are desired. For example, although Alan P. Kozikowski
Alan P. Kozikowski is an American medicinal chemist, drug designer, and pharmaceutical entrepreneur, best known for his research on 5-HT receptors, and GSK-3 inhibitors. He is an author of a book ''Drug Design for Neuroscience''. He has over 10 ...
showed that ''R/S'' nocaine is less addictive than ''SS'' Nocaine, studies on variously substituted phenyltropanes by F. Ivy Carroll ''et at.'' revealed that the ββ isomers were less likely to cause convulsions
A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a ...
, tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, f ...
and death
Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...
than the corresponding ''trans'' isomers (more specifically, what is meant is the 1''R'',2''R'',3''S'' isomers). While it does still have to be conceded that RTI-55
RTI(-''4229'')-55, also called RTI-55 or iometopane, is a phenyltropane-based psychostimulant used in scientific research and in some medical applications. This drug was first cited in 1991. RTI-55 is a non-selective dopamine reuptake inhibitor d ...
caused death at a dosage of 100 mg/kg, it's therapeutic index of safety is still much better than the corresponding ''trans'' isomers because it is more potent compound.
In discussing cocaine and related compounds such as amphetamines, it is clear that these psychostimulants cause increased blood pressure, decreased appetite
Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to reg ...
(and hence weight loss
Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other con ...
), increased locomotor activity (LMA) etc. In the United States, cocaine overdose is one of the leading causes of ER admissions each year due to drug overdose. People are at increased risk of heart attack and stroke and also present with an array of psychiatric symptoms including anxiety & paranoia etc. On removal of the 2C tropane bridge and on going from RTI-31 to the simpler ''SS'' and ''RS'' Nocaine it was seen that these compounds still possessed activity as NDRIs but were not powerful psychostimulants. Hence, this might be viewed as a strategy for increasing the safety of the compounds and would also be preferable to use in patients who are not looking to achieve weight loss.
In light of the above paragraph, another way of reducing the psychomotor stimulant and addictive qualities of phenyltropane stimulants is in picking one that is relatively serotonergic. This strategy was employed with success for RTI-112.[
Another thing that is important and should be mentioned is the risk for ]serotonin syndrome
Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs. The degree of symptoms can range from mild to severe, including a potentiality of death. Symptoms in mild cases include h ...
when incorporating the element of 5-HT transporter inhibition into a compound that is already fully active as a NDRI (or vice versa). The reasons for serotonin syndrome
Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs. The degree of symptoms can range from mild to severe, including a potentiality of death. Symptoms in mild cases include h ...
are complicated and not fully understood.
Addiction
Drug addiction may be regarded as a disease of the brain reward system. This system, closely related to the system of emotional arousal, is located predominantly in the limbic structures of the brain. Its existence was proved by demonstration of the "pleasure centers," that were discovered as the location from which electrical self-stimulation is readily evoked. The main neurotransmitter involved in the reward is dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...
, but other monoamines and acetylcholine
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
may also participate. The anatomical core of the reward system are dopaminergic neurons of the ventral tegmentum that project to the nucleus accumbens
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypot ...
, amygdala
The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex v ...
, prefrontal cortex
In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA ...
and other forebrain structures.
There are several groups of substances that activate the reward system and they may produce addiction, which in humans is a chronic, recurrent disease, characterized by absolute dominance of drug-seeking behavior.[
According to various studies, the relative likelihood of rodents and non-human primates self-administering various psychostimulants that modulate monoaminergic neurotransmission is lessened as the dopaminergic compounds become more serotonergic.
The above finding has been found for amphetamine and some of its variously substituted analogs including ]PAL-287
Naphthylaminopropane (PAL-287) is an experimental drug under investigation as of 2007 for the treatment of alcohol and stimulant addiction.
Naphthylisopropylamine acts as a non-neurotoxic releasing agent of serotonin, norepinephrine, and dopamin ...
etc.
RTI-112 is another good example of the compound becoming less likely to be self-administered by the test subject in the case of a dopaminergic compound that also has a marked affinity for the serotonin transporter.
WIN 35428, RTI-31
(–)-2β-Carbomethoxy-3β-(4'-chlorophenyl)tropane (RTI-''4229''-31) is a synthetic structural analog, analog of cocaine that acts as a stimulant. Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. A ...
, RTI-51 and RTI-55
RTI(-''4229'')-55, also called RTI-55 or iometopane, is a phenyltropane-based psychostimulant used in scientific research and in some medical applications. This drug was first cited in 1991. RTI-55 is a non-selective dopamine reuptake inhibitor d ...
were all compared and it was found that there was a negative correlation between the size of the halogen atom and the rate of self-administration (on moving across the series). Rate of onset was held partly accountable for this, although increasing the potency of the compounds for the serotonin transporter also played a role.
Further evidence that 5-HT dampens the reinforcing actions of dopaminergic medications comes from the co-administration of psychostimulants with SSRIs, and the phen/fen combination was also shown to have limited abuse potential relative to administration of phentermine only.
NET blockade is unlikely to play a major role in mediating addictive behavior. This finding is based on the premise that desipramine is not self-administered, and also the fact that the NRI atomoxetine
Atomoxetine, sold under the brand name Strattera, among others, is a medication used to treat attention deficit hyperactivity disorder (ADHD). It may be used alone or along with psychostimulants. It is also used as a cognitive enhancer to impr ...
was not reinforcing. However, it was still shown to facilitate dopaminergic neurotransmission in certain brain regions such as in the core of the PFC.
Relation to cocaine
Cocaine
Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...
is a short-acting SNDRI that also exerts auxiliary pharmacological actions on other receptors. Cocaine is a relatively "balanced" inhibitor, although facilitation of dopaminergic neurotransmission is what has been linked to the reinforcing and addictive effects. In addition, cocaine has some serious limitations in terms of its cardiotoxicity due to its local anesthetic
A local anesthetic (LA) is a medication that causes absence of pain sensation. In the context of surgery, a local anesthetic creates an absence of pain in a specific location of the body without a loss of consciousness, as opposed to a general an ...
activity. Thousands of cocaine users are admitted to emergency units in the USA every year because of this; thus, development of safer substitute medications for cocaine abuse could potentially have significant benefits for public health.
Many of the SNDRIs currently being developed have varying degrees of similarity to cocaine in terms of their chemical structure
A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of a ...
. There has been speculation over whether the new SNDRIs will have an abuse potential like cocaine does. However, for pharmacotherapeutical treatment of cocaine addiction it is advantageous if a substitute medication is at least weakly reinforcing because this can serve to retain addicts in treatment programmes:
However, not all SNDRIs are reliably self-administered by animals. Examples include:
* PRC200-SS was not reliably self-administered.[
* RTI-112 was not self-administered][ because at low doses the compound preferentially occupies the SERT and not the DAT.]
* Tesofensine
Tesofensine (NS2330) is a serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity. Tesofensine was originally developed by a Danish biotechnology compa ...
was also not reliably self-administered by human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
stimulant
Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
addicts.
* The nocaine
(+)-CPCA (nocaine, 3α-carbomethoxy-4β-(4-chlorophenyl)-''N''-methylpiperidine aka CTDP 31,446
) is a stimulant drug similar in structure to pethidine (an opioid that possesses NDRI actions) and to RTI-31, but nocaine is lacking the two-carbo ...
analog JZAD-IV-22 only partly substituted for cocaine in animals, but produced none of the psychomotor activation of cocaine, which is a trait marker for stimulant addiction.[
]
Legality
Cocaine
Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...
is a controlled drug (Class A in the UK; Schedule II in the USA); it has not been entirely outlawed in most countries, as despite having some "abuse potential" it is recognized that it does have medical uses.
Brasofensine was made "class A" in the UK under the MDA (misuse of drugs act). The semi-synthetic procedure for making BF uses cocaine as the starting material.
Naphyrone first appeared in 2006 as one of quite a large number of analogs of pyrovalerone designed by the well-known medicinal chemist P. Meltzer ''et al.''[ When the ]designer drug
A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. Des ...
s mephedrone and methylone
Methylone (also known as "3,4-methylenedioxy-''N''-methylcathinone", "MDMC", "βk-MDMA" and by the slang term "M1") is an empathogen and stimulant psychoactive drug. It is a member of the substituted amphetamine, substituted cathinone and s ...
became banned in the United Kingdom, vendors of these chemicals needed to find a suitable replacement. Mephedrone and methylone affect the same chemicals in the brain as a SNDRI, although they are thought to act as monoamine ''releasers'' and not act through the reuptake inhibitor mechanism of activity. A short time later, mephedrone and methylone were banned (which had become quite popular by the time they were illegalized), naphyrone appeared under the trade name NRG-1.[ NRG-1 was promptly illegalized, although it is not known if its use resulted in any hospitalizations or deaths.
]
Role of monoamine neurotransmitters
Monoamine hypothesis
The original monoamine hypothesis
Scientific studies have found that different brain areas show altered activity in humans with major depressive disorder (MDD), and this has encouraged advocates of various theories that seek to identify a biochemical origin of the disease, as opp ...
postulates that depression is caused by a deficiency or imbalances in the monoamine neurotransmitters (5-HT, NE, and DA). This has been the central topic of depression research for approximately the last 50 years; it has since evolved into the notion that depression arises through alterations in target neurons (specifically, the dendrites) in monoamine pathways.
When reserpine
Reserpine is a drug that is used for the treatment of high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diuretic reduces m ...
(an alkaloid
Alkaloids are a class of basic
BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Th ...
with uses in the treatment of hypertension and psychosis
Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...
) was first introduced to the West from India
India, officially the Republic of India ( Hindi: ), is a country in South Asia. It is the seventh-largest country by area, the second-most populous country, and the most populous democracy in the world. Bounded by the Indian Ocean on the ...
in 1953, the drug was unexpectedly shown to produce depression-like symptoms. Further testing was able to reveal that reserpine causes a depletion of monoamine concentrations in the brain. Reserpine's effect on monoamine concentrations results from blockade of the vesicular monoamine transporter, leading to their increased catabolism by monoamine oxidase. However, not everyone has been convinced by claims that reserpine is depressogenic, some authors ( David Healy in particular) have even claimed that it is antidepressant.
Tetrabenazine, a similar agent to reserpine, which also depletes catecholamine stores, and to a lesser degree 5-HT, was shown to induce depression in many patients.[
Iproniazid, an inhibitor of MAO, was noted to elevate mood in depressed patients in the early 1950s, and soon thereafter was shown to lead to an increase in NA and 5-HT.][
Hertting et al. demonstrated that the first TCA, imipramine, inhibited cellular uptake of NA in peripheral tissues. Moreover, both antidepressant agents were demonstrated to prevent reserpine-induced sedation. Likewise, administration of DOPA to laboratory animals was shown to reverse reserpine induced sedation; a finding reproduced in humans. Amphetamine, which releases NA from vesicles and prevents re-uptake was also used in the treatment of depression at the time with varying success.]
In 1965 Schildkraut formulated the catecholamine
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol ( benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a ...
theory of depression. This was subsequently the most widely cited article in the American Journal of Psychiatry
''The American Journal of Psychiatry'' is a monthly peer-reviewed medical journal covering all aspects of psychiatry, and is the official journal of the American Psychiatric Association.
The first volume was issued in 1844, at which time it was k ...
. The theory stated that "some, if not all, depressions are associated with an absolute or relative deficiency of catecholamines, in particular noradrenaline (NA), at functionally important adrenergic receptor sites in the brain. However, elation may be associated with an excess of such amines."
Shortly after Schildkraut's catecholamine hypothesis was published, Coppen proposed that 5-HT, rather than NA, was the more important neurotransmitter in depression. This was based on similar evidence to that which produced the NA theory as reserpine, imipramine, and iproniazid affect the 5-HT system, in addition to the noradrenergic system. It was also supported by work demonstrating that if catecholamine levels were depleted by up to 20% but 5-HT neurotransmission remained unaltered there was no sedation in animals. Alongside this, the main observation promoting the 5-HT theory was that administration of a MAOI in conjunction with tryptophan (precursor of 5-HT) elevated mood in control patients and potentiated the antidepressant effect of MAOI. Set against this, combination of an MAOI with DOPA did not produce a therapeutic benefit.[
Inserting a chlorine atom into imipramine leads to clomipramine, a drug that is much more SERT selective than the parent compound.][
Clomipramine was a predecessor to the development of the more recent SSRIs. There was, in fact, a time prior to the SSRIs when selective NRIs were being considered (c.f. talopram and melitracen). In fact, it is also believed that the selective NRI nisoxetine was discovered prior to the invention of ]fluoxetine
Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...
. However, the selective NRIs did not get promoted in the same way as did the SSRIs, possibly due to an increased risk of suicide. This was accounted for on the basis of the energizing effect that these agents have. Moreover, NRIs have the additional adverse safety risk of hypertension that is not seen for SSRIs. Nevertheless, NRIs have still found uses.
Further support for the monoamine hypothesis came from monoamine depletion studies:
* Alpha-methyl-''p''-tyrosine ( AMPT) is a tyrosine hydroxylase enzyme inhibitor
An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a s ...
that serves to inhibit catecholamine synthesis. AMPT led to a resurgence of depressive symptoms in patients improved by the NE reuptake inhibitor (NRI) desipramine, but not by the SSRI fluoxetine. The mood changes induced by AMPT may be mediated by decreases in norepinephrine, while changes in selective attention and motivation may be mediated by dopamine.
* Dietary depletion of the DA precursors phenylalanine and tyrosine does not result in the relapse of formerly depressed patients off their medication.
* Administration of fenclonine (''para''-chlorophenylalanine) is able to bring about a depletion of 5-HT. The mechanism of action for this is via tryptophan hydroxylase inhibition. In the 1970s administration of parachlorophenylalanine produced a relapse in depressive symptoms of treated patients, but it is considered too toxic for use today.
* Although depletion of tryptophan
Tryptophan (symbol Trp or W)
is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromati ...
— the rate-limiting factor of serotonin synthesis — does not influence the mood of healthy volunteers and untreated patients with depression, it does produce a rapid relapse of depressive symptoms in about 50% of remitted patients who are being, or have recently been treated with serotonin selective antidepressants.
Dopaminergic
There appears to be a pattern of symptoms that are currently inadequately addressed by serotonergic antidepressants – loss of pleasure (anhedonia), reduced motivation, loss of interest, fatigue and loss of energy, motor retardation, apathy and hypersomnia. Addition of a pro-dopaminergic component into a serotonin based therapy would be expected to address some of these short-comings.
Several lines of evidence suggest that an attenuated function of the dopaminergic system may play an important role in depression:
* Mood disorders are highly prevalent in pathologies characterized by a deficit in central DA transmission such as Parkinson's disease (PD). The prevalence of depression can reach up to 50% of individuals with PD.
* Patients taking strong dopaminergic antagonists such as those used in the treatment of psychosis are more likely than the general population to develop symptoms of depression.
* Data from clinical studies have shown that DA agonists, such as bromocriptine
Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic mali ...
, pramipexole
Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipe ...
and ropinirole
Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In PD the dose needs to be adjusted to the effect and treatment should not be suddenly stopped. ...
, exhibit antidepressant properties.
* Amineptine, a TCA-derivative that predominantly inhibits DA re-uptake and has minimal noradrenergic and serotonergic activity has also been shown to possess antidepressant activity. A number of studies have suggested that amineptine has similar efficacy to the TCAs, MAOIs and SSRIs. However, amineptine is no longer available as a treatment for depression due to reports of an abuse potential.
* The B-subtype selective MAOI selegiline
Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It is provided in the form of a capsule or ...
(a drug developed for the treatment of PD) has now been approved for the treatment of depression in the form of a transdermal
Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery.
The drug is administered in the form of a patch or ointme ...
patch (Emsam
Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It is provided in the form of a capsule or ...
). For some reason, there have been numerous reports of users taking this drug in conjunction with β-phenethylamine
Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace am ...
.
* Taking psychostimulants for the alleviation of depression is well proven strategy, although in a clinical setting the use of such drugs is usually prohibited because of their strong addiction propensity.
* When users withdraw from psychostimulant drugs of abuse (in particular, amphetamine), they experience symptoms of depression. This is likely because the brain enters into a hypodopaminergic state, although there might be a role for noradrenaline also.
For these drugs to be reinforcing, they must block more than 50% of the DAT within a relatively short time period (<15 minutes from administration) and clear the brain rapidly to enable fast repeated administration.
In addition to mood, they may also improve cognitive performance, although this remains to be demonstrated in humans.
The rate of clearance from the body is faster for ritalin than it is for regular amphetamine.
Noradrenergic
The decreased levels of NA proposed by Schildkraut, suggested that there would be a compensatory upregulation of β-adrenoceptors. Despite inconsistent findings supporting this, more consistent evidence demonstrates that chronic treatment with antidepressants and electroconvulsive therapy (ECT) decrease β-adrenoceptor density in the rat forebrain. This led to the theory that β-adrenoceptor downregulation was required for clinical antidepressant efficacy. However, some of the newly developed antidepressants do not alter, or even increase β-adrenoceptor density.[
Another adrenoceptor implicated in depression is the presynaptic α2-adrenoceptor. Chronic desipramine treatment in rats decreased the sensitivity of α2-adrenoceptors, a finding supported by the fact that clonidine administration caused a significant increase in growth hormone (an indirect measure of α2-adrenoceptor activity) although platelet studies proved inconsistent. This supersensitivity of α2-adrenoceptor was postulated to decrease locus coeruleus (the main projection site of NA in the central nervous system, CNS) NA activity leading to depression.
In addition to enhancing NA release, α2-adrenoceptor antagonism also increases serotonergic neurotransmission due to blockade of α2-adrenoceptors present on 5-HT nerve terminals.
]
Serotonergic
5-Hydroxytryptamine (5-HT or serotonin) is an important cell-to-cell signaling molecule found in all animal phyla. In mammals, substantial concentrations of 5-HT are present in the central and peripheral nervous systems, gastrointestinal tract and cardiovascular system. 5-HT is capable of exerting a wide variety of biological effects by interacting with specific membrane-bound receptors, and at least 13 distinct 5-HT receptor subtypes have been cloned and characterized. With the exception of the 5-HT3 receptor subtype, which is a transmitter-gated ion channel, 5-HT receptors are members of the 7-transmembrane G protein-coupled receptor superfamily. In humans, the serotonergic system is implicated in various physiological processes such as sleep-wake cycles, maintenance of mood, control of food intake and regulation of blood pressure. In accordance with this, drugs that affect 5-HT-containing cells or 5-HT receptors are effective treatments for numerous indications, including depression, anxiety, obesity, nausea, and migraine.
Because serotonin and the related hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
melatonin
Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle.
In vertebrat ...
are involved in promoting sleep, they counterbalance the wake-promoting action of increased catecholaminergic neurotransmission. This is accounted for by the lethargic feel that some SSRIs can produce, although TCAs and antipsychotics can also cause lethargy albeit through different mechanisms.
Appetite suppression is related to 5-HT2C receptor activation as for example was reported for PAL-287 recently.
Activation of the 5-HT2C receptor has been described as "panicogen" by users of ligands for this receptor (e.g., mCPP). Antagonism of the 5-HT2C receptor is known to augment dopaminergic output. Although SSRIs with 5-HT2C antagonist actions were recommended for the treatment of depression, 5-HT2C receptor agonists were suggested for treating cocaine addiction since this would be anti-addictive. Nevertheless, the 5-HT2C is known to be rapidly downregulated upon repeated administration of an agonist agent, and is actually antagonized.
Azapirone-type drugs (e.g., buspirone), which act as 5-HT1A receptor agonists and partial agonists have been developed as anxiolytic agents that are not associated with the dependence and side-effect profile of the benzodiazepines. The hippocampal neurogenesis produced by various types of antidepressants, likewise, is thought to be mediated by 5-HT1A receptors. Systemic administration of a 5-HT1A agonist also induces growth hormone
Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...
and adrenocorticotropic hormone
Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
(ACTH) release through actions in the hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...
.
Current antidepressants
Most antidepressants on the market today target the monoaminergic system.
SSRIs
The most commonly prescribed class of antidepressants in the USA today are the selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.
SSRIs increase the extracellul ...
s (SSRIs). These drugs inhibit the uptake of the neurotransmitter 5-HT by blocking the SERT, thus increasing its synaptic concentration, and have shown to be efficacious in the treatment of depression, however sexual dysfunction
Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction ...
and weight gain
Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition.
Description
Weight gain occurs ...
are two very common side-effects that result in discontinuation of treatment.
Although many patients benefit from SSRIs, it is estimated that approximately 50% of depressive individuals do not respond adequately to these agents. Even in remitters, a relapse is often observed following drug discontinuation. The major limitation of SSRIs concerns their delay of action. It appears that the clinical efficacy of SSRIs becomes evident only after a few weeks.
SSRIs can be combined with a host of other drugs including bupropion
Bupropion, sold under the brand names Wellbutrin and Zyban among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cas ...
, α2 adrenergic antagonists (e.g., yohimbine) as well as some of the atypical antipsychotics. The augmentation agents are said to behave synergistically with the SSRI although these are clearly of less value than taking a single compound that contains all of the necessary pharmacophoric elements relative to the consumption of a mixture of different compounds. It is not entirely known what the reason for this is, although ease of dosing is likely to be a considerable factor. In addition, single compounds are more likely to be approved by the FDA than are drugs that contain greater than one pharmaceutical ingredient (polytherapies).
A number of SRIs were under development that had auxiliary interactions with other receptors. Particularly notable were agents behaving as co-joint SSRIs with additional antagonist activity at 5-HT1A receptors. 5-HT1A receptors are located presynaptically as well as post-synaptically. It is the presynaptic receptors that are believed to function as autoreceptors (cf. studies done with pindolol). These agents were shown to elicit a more robust augmentation in the % elevation of extracellular 5-HT relative to baseline than was the case for SSRIs as measured by in vivo microdialysis.[
]
NRIs
Norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epine ...
s (NRIs) such as reboxetine prevent the reuptake of norepinephrine, providing a different mechanism of action to treat depression. However reboxetine is no more effective than the SSRIs in treating depression. In addition, atomoxetine
Atomoxetine, sold under the brand name Strattera, among others, is a medication used to treat attention deficit hyperactivity disorder (ADHD). It may be used alone or along with psychostimulants. It is also used as a cognitive enhancer to impr ...
has found use in the treatment of ADHD as a non-addictive alternative to Ritalin. The chemical structure of atomoxetine is closely related to that of fluoxetine
Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...
(an SSRI) and also duloxetine (SNRI).
NDRIs
Bupropion
Bupropion, sold under the brand names Wellbutrin and Zyban among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cas ...
is a commonly prescribed antidepressant that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It prevents the reuptake of NA and DA (weakly) by blocking the corresponding transporters, leading to increased noradrenergic and dopaminergic neurotransmission. This drug does not cause sexual dysfunction or weight gain like the SSRIs but has a higher incidence of nausea. Methylphenidate
Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent ...
is a much more reliable example of an NDRI (the action that it displays on the DAT usually getting preferential treatment). Methylphenidate is used in the treatment of ADHD, its use in treating depression is not known to have been reported, it is presumed owing to its psychomotor activating effects and it functioning as a positive reinforcer. There are also reports of methylphenidate being used in the treatment of psychostimulant addiction, in particular cocaine addiction, since the addictive actions of this drug are believed to be mediated by the dopamine neurotransmitter.
SNRIs
Serotonin–norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine
Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic di ...
(Effexor), its active metabolite desvenlafaxine
Desvenlafaxine, sold under the brand name Pristiq among others, is a medication used to treat depression. It is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class and is taken by mouth. It is recommended that the ...
(Pristiq), and duloxetine (Cymbalta) prevent the reuptake of both serotonin and norepinephrine, however their efficacy appears to be only marginally greater than the SSRIs.
Sibutramine is the name of an SNRI based appetite suppressant with use in the treatment of obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
. This was explored in the treatment of depression, but was shown not to be effective.
Both sibutramine and venlafaxine
Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic di ...
are phenethylamine
Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace am ...
-based. At high doses, both venlafaxine and sibutramine will start producing dopaminergic effects. The inhibition of DA reuptake is unlikely to be relevant at clinically approved doses.
MAOIs
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, esp ...
s (MAOIs) were the first antidepressants to be introduced. They were discovered entirely by serendipity.[ Iproniazide (the first MAOI) was originally developed as an antitubercular agent but was then unexpectedly found to display antidepressant activity.
Isoniazid also displayed activity as an antidepressant, even though it is not a MAOI. This led some people to question whether it is some property of the hydrazine, which is responsible for mediating the antidepressant effect, even going as far as to state that the MAOI activity could be a secondary side-effect. However, with the discovery of tranylcypromine (the first non-hydrazine MAOI), it was shown that MAOI is thought to underlie the antidepressant bioactivity of these agents. Etryptamine is another example of a non-hydrazine MAOI that was introduced.
The MAOIs work by inhibiting the monoamine oxidase enzymes that, as the name suggests, break down the monoamine neurotransmitters. This leads to increased concentrations of most of the monoamine neurotransmitters in the human brain, serotonin, norepinephrine, dopamine and melatonin. The fact that they are more efficacious than the newer generation antidepressants is what leads scientists to develop newer antidepressants that target a greater range of neurotransmitters. The problem with MAOIs is that they have many potentially dangerous side-effects such as hypotension, and there is a risk of food and drug interactions that can result in potentially fatal serotonin syndrome or a hypertensive crisis. Although selective MAOIs can reduce, if not eliminate these risks, their efficacy tends to be lower.
MAOIs may preferentially treat TCA-resistant depression, especially in patients with features such as fatigue, volition inhibition, motor retardation and hypersomnia. This may be a function of the ability of MAOIs to increase synaptic levels of DA in addition to 5-HT and NE. The MAOIs also seem to be effective in the treatment of fatigue associated with fibromyalgia (FM) or chronic fatigue syndrome (CFS).
Although a substantial number of MAOIs were approved in the 1960s, many of these were taken off the market as rapidly as they were introduced. The reason for this is that they were ]hepatotoxic
Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn f ...
and could cause jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme met ...
.
TCAs
The first tricyclic antidepressant
Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and we ...
(TCA), imipramine
Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. The drug is also used to treat bedwetting. ...
(Tofranil), was derived from the antipsychotic
Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range o ...
drug chlorpromazine
Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar di ...
, which was developed as a useful antihistaminergic agent with possible use as a hypnotic sedative.[ Imipramine is an iminodibenzyl (]dibenzazepine
Dibenzazepine (iminostilbene) is a chemical compound with two benzene rings fused to an azepine group.
See also
* Benzazepine
* Dibenzothiazepine
* Dibenzothiepin
* Dibenzoxepin
Dibenzoxepin, or dibenz 'b'',''e''xepin, is a tricyclic compoun ...
).
The TCAs such as imipramine and amitriptyline typically prevent the reuptake of serotonin or norepinephine.
It is the histaminiergic (H1), muscarinic acetylcholinergic (M1), and alpha adrenergic (α1) blockade that is responsible for the side-effects of TCAs. These include somnolence and lethargy, anticholinergic side-effects, and hypotension. Due to the narrow gap between their ability to block the biogenic amine uptake pumps versus the inhibition of fast sodium channels, even a modest overdose of one of the TCAs could be lethal. TCAs were, for 25 years, the leading cause of death from overdoses in many countries. Patients being treated with antidepressants are prone to attempt suicide and one method they use is to take an overdose of their medications.
Another example of a TCA is amineptine which is the only one believed to function as a DRI. It is no longer available.
Failure of SNDRIs for depression
SNDRIs have been under investigation for the treatment of major depressive disorder for a number of years but, as of 2015, have failed to meet effectiveness expectations in clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s. In addition, the augmentation of a selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.
SSRIs increase the extracellul ...
(SSRI) or serotonin-norepinephrine reuptake inhibitor with lisdexamfetamine, a norepinephrine–dopamine releasing agent, recently failed to separate from placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
in phase III clinical trials of individuals with treatment-resistant depression
Treatment-resistant depression is a term used in psychiatry to describe people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time. Definitions of treatment- ...
, and clinical development was subsequently discontinued. These occurrences have shed doubt on the potential benefit of dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate do ...
augmentation of conventional serotonergic
Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chem ...
and noradrenergic antidepressant therapy. As such, skepticism has been cast on the promise of the remaining SNDRIs that are still being trialed, such as ansofaxine (currently in phase II Phase II, Phase 2 or Phase Two may refer to:
Media
* Marvel Cinematic Universe: Phase Two, six American superhero films from 2013–2015
* ''Star Trek: Phase II'', an unrealized television series based on the characters of Gene Roddenberry's ''S ...
trials), in the treatment of depression. Nefazodone a weak SNDRI has been successful in treating major depressive disorder which makes it unique.
See also
* Monoamine reuptake inhibitor
References
External links
*
{{DEFAULTSORT:Serotonin-norepinephrine-dopamine reuptake inhibitor