Dopamine partial agonists
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A dopamine agonist (DA) is a compound that activates
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used to treat Parkinson's disease. They are also used, to a far lesser extent, in treating hyperprolactinemia and restless legs syndrome. They are not intended for treatment of clinical depression, and studies have shown severe detrimental side effects resulting from off-label use of dopamine agonists in treating depression, particularly in their tendency to produce
impulse control disorder Impulse-control disorder (ICD) is a class of psychiatric disorders characterized by impulsivity – failure to resist a temptation, an urge, or an impulse; or having the inability to not speak on a thought. Many psychiatric disorders feature imp ...
s and extreme cases of
withdrawal syndrome Drug withdrawal, drug withdrawal syndrome, or substance withdrawal syndrome, is the group of symptoms that occur upon the abrupt discontinuation or decrease in the intake of pharmaceutical or recreational drugs. In order for the symptoms of wit ...
.


Medical uses


Parkinson's disease

Dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
s are mainly used in the treatment of Parkinson's disease.  The cause of Parkinson's is not fully known but genetic factors, for example specific genetic mutations, and environmental triggers have been linked to the disease. In Parkinson's disease
dopaminergic neurons Dopaminergic cell groups, DA cell groups, or dopaminergic nuclei are collections of neurons in the central nervous system that synthesize the neurotransmitter dopamine. In the 1960s, dopaminergic neurons or ''dopamine neurons'' were first ident ...
that produce the
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. Neuro ...
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
in the brain slowly break down and can eventually die. With decreasing levels of dopamine the brain can't function properly and causes abnormal brain activity, which ultimately leads to the symptoms of Parkinson's disease. There are two fundamental ways of treating Parkinson's disease, either by replacing dopamine or mimicking its effect. Dopamine agonists act directly on the dopamine receptors and mimic dopamine's effect. Dopamine agonists have two subclasses: ergoline and non ergoline agonists. Both subclasses target dopamine D2-type receptors. Types of ergoline agonists are cabergoline and bromocriptine and examples of non-ergoline agonists are pramipexole, ropinirole and rotigotine. Ergoline agonists are much less used nowadays because of the risk of
cartilage Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...
formation in heart valves.


Treatment of depression in Parkinson's patients

Depressive symptoms Depression is a mental state of low Mood (psychology), mood and aversion to activity, which affects more than 280 million people of all ages (about 3.5% of the global population). Classified medically as a mental disorder, mental and Abnor ...
and disorders are common in patients with Parkinson's disease and can affect their quality of life. Increased anxiety can accentuate the symptoms of Parkinson's and is therefore essential to treat. Instead of conventional antidepressant medication in treating depression, treatment with dopamine agonists has been suggested. It is mainly thought that dopamine agonists help with treating depressive symptoms and disorders by alleviating motor complications, which is one of the main symptoms of Parkinson's disease.  Although preliminary evidence of clinical trials has shown interesting results, further research is crucial to establish the anti-depressive effects of dopamine agonists in treating depressive symptoms and disorders in those with Parkinson's.


Hyperprolactinemia

Dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
is a prolactin-inhibiting factor (PIFs) since it lowers the prolactin-releasing factors (PRFs) synthesis and secretion through D2-like receptors. That is why dopamine agonists are the first-line treatment in hyperprolactinemia. Ergoline-derived agents, bromocriptine and cabergoline are mostly used in treatment. Research shows that these agents reduce the size of prolactinomas by suppressing the hypersecretion of prolactin resulting in normal
gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sper ...
al function.


Restless leg syndrome

Numerous clinical trials have been performed to assess the use of dopamine agonists for the treatment of restless leg syndrome (RLS). RLS is identified by the strong urge to move and is a dopamine-dependent disorder. RLS symptoms decrease with the use of drugs that stimulate dopamine receptors and increase dopamine levels, such as dopamine agonists.


Adverse effects


Side effects

Dopamine agonists are mainly used to treat Parkinson’s disease but are also used to treat hyperprolactinemia and restless legs syndrome. The side effects are mainly recorded in treatment for Parkinson’s disease where dopamine agonists are commonly used, especially as first-line treatment with
levodopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
. Dopamine agonists are divided into two subgroups or drug classes, first-generation and newer agents. Ergoline derived agonists are the first generation and are not used as much as the newer generation the non-ergoline derived agonists. Ergoline derived agonists are said to be "dirtier" drugs because of their interaction with other receptors than dopamine receptors, therefore they cause more side effects. Ergoline derived agonists are for example bromocriptine, cabergoline, pergolide and
lisuride Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth. Side effects of lis ...
. Non-ergoline agonists are pramipexole, ropinirole, rotigotine, piribedil and apomorphine. The most common adverse effects are constipation, nausea and
headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...
s. Other serious side effects are hallucinations, peripheral edema, gastrointestinal ulcers, pulmonary fibrosis and psychosis. Dopamine agonists have been linked to cardiac problems. Side effects such as hypotension, myocardial infarction, congestive heart failure, cardiac fibrosis, pericardial effusion and tachycardia. A high risk for valvular heart disease has been established in association with ergot-derived agonists especially in elderly patients with hypertension. Somnolence and sleep attacks have been reported as an adverse effect that happen to almost 30% of patients using dopamine agonists. Daytime sleepiness, insomnia and other sleep disturbances have been reported as well.
Impulse control disorder Impulse-control disorder (ICD) is a class of psychiatric disorders characterized by impulsivity – failure to resist a temptation, an urge, or an impulse; or having the inability to not speak on a thought. Many psychiatric disorders feature imp ...
that is described as gambling, hypersexuality, compulsive shopping and binge eating is one serious adverse effect of dopamine agonists. After long-term use of dopamine agonist a
withdrawal syndrome Drug withdrawal, drug withdrawal syndrome, or substance withdrawal syndrome, is the group of symptoms that occur upon the abrupt discontinuation or decrease in the intake of pharmaceutical or recreational drugs. In order for the symptoms of wit ...
may occur when discontinuing or during dose reduction. The following side effects are possible: anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalised pain, and drug cravings. For some individuals, these withdrawal symptoms are short-lived and make a full recovery, for others a protracted withdrawal syndrome may occur with withdrawal symptoms persisting for months or years.


Interactions

Dopamine agonists
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with a number 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 insuffla ...
s but there is little evidence that they
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with other Parkinson’s drugs. In most cases there is no reason not to co-administer Parkinson's drugs. Although there has been an indication that the use of dopamine agonists with L-DOPA can cause psychosis therefore it is recommended that either the use of dopamine agonists be discontinued or the dose of L-DOPA reduced. Since ergot-dopamine
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
have antihypertensive qualities it is wise to monitor
blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
when using dopamine agonists with
antihypertensive Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests tha ...
drugs to ensure that the patient does not get hypotension. That includes the drug
sildenafil Sildenafil, sold under the brand name Viagra, among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. It is unclear if it is effective for treating sexual dysfunction in women. It is taken by ...
which is commonly used to treat
erectile dysfunction Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of male ...
but also used for pulmonary hypertension. There is evidence that suggests that since ergot dopamine agonists are
metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
by
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
enzyme concentration rises with the use of CYP3A4 inhibitors. For example, in one study bromocriptine was given with a CYP3A4 inhibitor and the AUC (e. Area under the curve) increased 268%. Ropinirole is a non-ergot derived dopamine
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
and concomitant use with a CYP1A2 inhibitor can result in a higher concentration of ropinirole. When discontinuing the CYP1A2 inhibitor, if using both drugs, there is a change that a dose adjustment for ropinirole is needed. There is also evidence the dopamine agonists inhibit various CYP enzymes and therefore they may inhibit the metabolism of certain drugs.


Pharmacology


Ergoline class


Pharmacokinetics of Bromocriptine

The
absorption Absorption may refer to: Chemistry and biology * Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which ...
of the oral dose is approximately 28% however, only 6% reaches the systemic circulation unchanged, due to a substantial
first-pass effect The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemi ...
. Bromocriptine reaches mean peak plasma levels in about 1–1.5 hours after a single oral dose. The drug has high
protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse th ...
, ranging from 90-96% bound to serum albumin. Bromocriptine is
metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
by
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
and excreted primarily in the
feces Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a relati ...
via biliary secretion. Metabolites and parent drugs are mostly
excreted Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...
via the liver, but also 6% via the kidney. It has a half-life of 2–8 hours.


Pharmacokinetics of Pergolide

Pergolide has a long half-life of about 27 hours and reaches a mean peak plasma level in about 2–3 hours after a single oral dose. The protein binding is 90% and the drug is mainly metabolized in the liver by CYP3A4 and CYP2D6. The major route of excretion is through the kidneys.


Non-Ergoline class


Pharmacokinetics of Pramipexole

Pramipexole reaches maximum plasma concentration 1–3 hours post-dose. It is about 15% bound to plasma proteins and the metabolism is minimal. Pramipexole has a long half-life, around 27 hours. The drug is mostly excreted in the urine, around 90%, but also in feces.


Pharmacokinetics of Ropinirole

Ropinirole is rapidly absorbed after a single oral dose, reaching plasma concentration in approximately 1–2 hours. The half-life is around 5–6 hours. Ropinirole is heavily metabolized by the liver and in vitro studies show that the enzyme involved in the metabolism of ropinirole is CYP1A2.


Pharmacokinetics of Rotigotine

Since rotigotine is a transdermal patch it provides continuous drug delivery over 24 hours. It has a half-life of 3 hours and the protein binding is around 92% in vitro and 89.5% in vivo. Rotigotine is extensively and rapidly metabolized in the liver and by the CYP enzymes. The drug is mostly excreted in urine (71%), but also in feces (23%).


Mechanism of action

The dopamine receptors are 7- transmembrane domains and are members of the G protein-coupled receptors (GPCR) superfamily. Dopamine receptors have five subtypes, D1 through D5, the subtypes can be divided into two subclasses due to their mechanism of action on adenylate cyclase enzyme, D1-like receptors (D1 and D5) and D2-like receptors (D2, D3 and D4). D1-like receptors are primarily coupled to Gαs/olf proteins and activates adenylate cyclase which increases intracellular levels of
cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
, they also activate the Gβγ complex and the N-type Ca2+ channel. D2-like receptors decrease intracellular levels of the second messenger cAMP by inhibiting adenylate cyclase.


Bromocriptine

Bromocriptine is an ergot derivative, semi-synthetic. Bromocriptine is a D2 receptor agonist and D1 receptor antagonist with a binding affinity to D2 receptors of anterior pituitary cells, exclusively on lactotrophs. Bromocriptine stimulates Na+, K+-ATPase activity and/or cytosolic Ca2+ elevation and therefore reduction of prolactin which leads to no production of cAMP.


Pramipexol

Pramipexol is a highly active non-ergot D2-like receptor agonist with a higher binding affinity to D3 receptors rather than D2 or D4 receptors. The mechanism of action of pramipexole is mostly unknown, it is thought to be involved in the activation of dopamine receptors in the area of the brain where the striatum and the substantia nigra is located. This stimulation of dopamine receptors in the striatum may lead to the better movement performance.


Structure–activity relationship

When dealing with agonists it can be extremely complex to confirm relationships between structure and biological activity. Agonists generate responses from
living tissues In biology, tissue is a biological organizational level between cells and a complete organ. A tissue is an ensemble of similar cells and their extracellular matrix from the same origin that together carry out a specific function. Organs are th ...
. Therefore, their activity depends both on their
efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a pragmatic clinical trial#Efficacy versu ...
to activate receptors and their affinity to bind to receptors.


Crossing the blood brain barrier

Many molecules are unable to cross the blood brain barrier (BBB). Molecules must be small, non-polar and lipophilic to cross over. If compounds do not possess these qualities they must have a specific transporter that can transport them over the BBB. Dopamine cannot diffuse across the BBB because of the catechol group, it is too polar and therefore unable to enter the brain. The catechol group is a dihydroxy benzene ring. The synthesis of dopamine consists of three stages. The synthesis process starts with an amino acid, called L-Tyrosine. In the second stage
Levodopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
(L-dopa) is formed by adding a phenol group to the benzene ring of L-Tyrosine. The formation of L-dopa from L-tyrosine is catalyzed by the enzyme tyrosine hydroxylase. The third stage is the formation of dopamine by removing the carboxylic acid group from L-dopa, catalysed by the enzyme dopa decarboxylase. Levodopa is also too polar to cross the blood brain barrier but it happens to be an amino acid so it has a specialized transporter called L-type amino acid transporter or LAT-1 that helps it diffuse through the barrier.


Dopamine

When dopamine interacts with ATP, which is a component of some dopamine receptors, it has a significant preference for a trans-conformation of the dopamine molecule. The dopamine-ATP complex is stabilised by
hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
ing between catechol hydroxyls and purine nitrogens and by electrostatic interactions between the protonated
ammonium The ammonium cation is a positively-charged polyatomic ion with the chemical formula or . It is formed by the protonation of ammonia (). Ammonium is also a general name for positively charged or protonated substituted amines and quaternary a ...
group of dopamine and a negative phosphate group. Two conformers of dopamine have been identified as alpha- and beta-conformers in which the catechol ring is coplanar with the plane of the
ethylamine Ethylamine, also known as ethanamine, is an organic compound with the formula CH3CH2NH2. This colourless gas has a strong ammonia-like odor. It condenses just below room temperature to a liquid miscible with virtually all solvents. It is a nucleo ...
side chain. They are substantial in agonist-receptor interactions.


Ergoline derivatives

Central dopaminergic agonist properties of semisynthetic ergoline derivatives lergotrile, pergolide, bromocriptine and
lisuride Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth. Side effects of lis ...
have been established. Some studies suggest that ergot alkaloids have the properties of mixed agonist-antagonist with regards to certain presynaptic and postsynaptic receptors. N-n- Propyl groups (chemical formula: –CH2CH2CH3) frequently enhance dopamine agonist effects in the ergoline derivatives. The (+)-
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 ...
displays notably diminished activity whereas the (-)-enantiomer possess potent dopamine agonist properties.


''Bromocriptine''

Bromocriptine has an ergot alkaloid structure. Ergot alkaloids are divided into 2 groups; amino acid ergot alkaloids and amine ergot alkaloids, bromocriptine is part of the former group. It contains a bromine
halogen The halogens () are a group in the periodic table consisting of five or six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), and tennessine (Ts). In the modern IUPAC nomenclature, this group is ...
on the ergot structure which increases the affinity for the D2-receptor but often reduces the efficacy. The similarity between the dopamine structure and the ergoline ring in bromocriptine is likely the cause for its action on the dopamine receptors. It has shown to have equal affinity for D2- and D3-receptor and much lower affinity for D1-receptor.


Non-ergoline derivatives

Non-ergoline dopamine receptor agonists have higher binding affinity to dopamine D3-receptors than dopamine D2-receptors. This binding affinity is related to D2 and D3 receptor homology, the homology between them has a high degree of sequence and is closest in their transmembrane domains, were they share around 75% of the amino acid.


''Apomorphine''

Apomorphine has a catechol element and belongs to a class called β-phenylethylamines and its main components are similar to the dopamine structure. The effect that apomorphine has on the dopamine receptors can also be linked to the similarities between its structure and dopamine. It is a chiral molecule and thus can be acquired in both the R and S form, the R form is the one that is used in therapy. When apomorphine interacts with the dopamine receptor, or the
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
on the receptor, the catechol and nitrogen are important to stabilize the structure with hydrogen bonding. The position of the hydroxyl groups is also important and monohydroxy derivatives have been found to be less potent than the dihydroxy groups. There are a number of stability concerns with apomorphine such as oxidation and racemization.


''Rotigotine''

Rotigotine is a phenolic amine and thus has poor oral bioavailability and fast clearance from the body. Therefore, it has been formulated as a transdermal patch, first and foremost to prevent
first pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the system ...
in the liver.


Members

Examples of dopamine agonists include:


Partial agonist

* Aripiprazole (Partial agonist of the D2 family receptors - Trade name "Abilify" in the United States; atypical antipsychotic) * Phencyclidine (a.k.a. PCP; partial agonist. Psychoactivity mainly due to NMDA antagonism) *
Quinpirole Quinpirole is a psychoactive drug and research chemical which acts as a selective D2 and D3 receptor agonist. It is used in scientific research. Quinpirole has been shown to increase locomotion and sniffing behavior in mice treated with it. At ...
(Partial agonist of the D2 and D3 family of receptors) * Salvinorin A (chief active constituent of the psychedelic herb
salvia divinorum ''Salvia divinorum'' (Latin: "sage of the diviners"; also called ska maría pastora, seer's sage, yerba de la pastora, magic mint or simply salvia) is a plant species with transient psychoactive properties when its leaves are consumed by che ...
, the psychoactivity of which is mainly due to Kappa-opioid receptor agonism; partial agonist at the D2 with an Intrinsic activity of 40-60%, binding affinity of Ki=5-10nM and EC50=50-90nM)


Agonists of full/unknown efficacy

* Apomorphine (Apokyn – used to treat Parkinson's disease & Restless leg syndrome ) – biased at the D1 receptor. * Bromocriptine (Parlodel – used to treat PD/ RLS) * Cabergoline (Dostinex – used to treat PD/RLS) *
Ciladopa Ciladopa (AY-27,110) is a dopamine agonist with a similar chemical structure to dopamine. It was under investigation as an antiparkinsonian agent but was discontinued due to concerns of tumorogenesis Carcinogenesis, also called oncogenesis ...
(used to treat PD/RLS) * Dihydrexidine (used to treat PD/RLS) *
Dinapsoline Dinapsoline is a drug developed for the treatment of Parkinson's disease, that acts as a selective full agonist at the dopamine D1 receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmen ...
(used to treat PD/RLS) *
Doxanthrine Doxanthrine is a synthetic compound which is a potent and selective full agonist for the dopamine D1 receptor. Doxanthrine has been shown to be orally active in producing contralateral rotation in the 6-hydroxydopamine rat model of Parkin ...
(used to treat PD/RLS) *
Epicriptine Epicriptine or ''beta''-dihydroergocryptine is a dopamine agonist of the ergoline class. It constitutes one third of the mixture known as dihydroergocryptine, the other two thirds consisting of ''alpha''-dihydroergocryptine. The ''alpha'' differ ...
(used to treat PD/RLS) *
Lisuride Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth. Side effects of lis ...
(used to treat PD/RLS) * Pergolide (used to treat PD/RLS) – previously available as Permax, but removed from the market in the USA on March 29, 2007. * Piribedil (Pronoran and Trivastal – used to treat PD/RLS) * Pramipexole (Mirapex and Sifrol – used to treat PD/RLS) *
Propylnorapomorphine N-n-Propylnorapomorphine (NPA) is an aporphine derivative dopamine agonist closely related to apomorphine. In rodents it has been shown to produce hyperactivity, stereotypy, hypothermia, antinociception, and penile erection, among other effects. N ...
(used to treat PD/RLS) *
Quinagolide Quinagolide (, ), sold under the brand name Norprolac, is a selective dopamine D2 receptor agonist which is used to reduce elevated levels of prolactin (hyperprolactinemia). It has also been found to be effective in the treatment of breast pa ...
(Norprolac – used to treat PD/RLS) * Ropinirole (Requip – used to treat PD/RLS) * Rotigotine (Neupro – used to treat PD/RLS) *
Roxindole Roxindole (EMD-49,980) is a dopaminergic and serotonergic drug which was originally developed by Merck KGaA for the treatment of schizophrenia. In clinical trials its antipsychotic efficacy was only modest but it was unexpectedly found to produc ...
(used to treat PD/RLS) *
Sumanirole Sumanirole (PNU-95,666) is a highly selective D2 receptor full agonist, the first of its kind to be discovered. It was developed for the treatment of Parkinson's disease and restless leg syndrome. While it has never been approved for medical us ...
(used to treat PD/RLS) Some, such as fenoldopam, are selective for dopamine receptor D1.


Related class of drugs: Indirect agonists

There are two classes of drugs that act as
indirect agonist In pharmacology, an indirect agonist or indirect-acting agonist is a substance that enhances the release or action of an endogenous neurotransmitter but has no specific agonist activity at the neurotransmitter receptor itself. Indirect agonists work ...
s of dopamine receptors: dopamine reuptake inhibitors and dopamine releasing agents. These are not considered dopamine agonists, since they have no specific agonist activity at dopamine receptors, but they are nonetheless related. Indirect agonists are prescribed for a wider range of conditions than standard dopamine agonists. The most commonly prescribed indirect agonists of dopamine receptors include: *
Amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
and/or dextroamphetamine (used to treat
ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...
, narcolepsy, and obesity) *
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 case ...
(used to facilitate smoking cessation and treat
nicotine addiction Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
and clinical depression) * Lisdexamfetamine (used to treat ADHD and binge eating disorder) * Methylphenidate or
dexmethylphenidate Dexmethylphenidate, sold under the brand name Focalin among others, is a strong central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years. If no benefit i ...
(used to treat ADHD and narcolepsy) Other examples include: *
Cathinone Cathinone (also known as benzoylethanamine, or β-keto-amphetamine) is a monoamine alkaloid found in the shrub '' Catha edulis'' (khat) and is chemically similar to ephedrine, cathine, methcathinone and other amphetamines. It is probably the m ...
* Cocaine ( anesthetic with no medical uses as a
central nervous system 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 ...
) *
Methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamph ...
(used in rare circumstances to treat ADHD and obesity) *
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 amin ...
(endogenous trace amine) * ''p''-Tyramine (endogenous trace amine)


History

Since the late 1960
Levodopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
(L-DOPA) has been used to treat Parkinson’s disease but there has always been a debate whether the treatment is worth the side effects. Around 1970 clinicians started using the dopamine agonist apomorphine alongside L-DOPA to minimize the side effects caused by L-DOPA, the dopamine agonists bind to the dopamine receptor in the absence of dopamine. Apomorphine had limited use since it had considerable side effects and difficulty with administration. In 1974 bromocriptine was use widely after clinicians discovered its benefits in treating Parkinsons. When using the two
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 insuffla ...
classes together there is a possibility to reduce the amount of L-DOPA by 20-30% and thus keeping the fluctuating motor responses to a minimum. Dopamine agonists are often used in younger people as monotherapy and as initial therapy instead of L-DOPA. Although it is important to know that there is a correlation between the two drugs, if l-DOPA doesn't work dopamine agonists are also ineffective. The early dopamine agonists, such as bromocriptine, were ergot derived and activated the D2-receptor. They induced major side effects such as fibrosis of cardiac valves. It is considered that the reason they induced such side effects is that they activate many types of receptors. Because of the major adverse effects of ergot derived dopamine agonists they are generally not used anymore and were mostly abandoned in favor of non-ergot agonists such as pramipexole, ropinirole and rotigotine. They do not induce as serious side effects although common side effects are nausea,
edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...
and hypotension. Patients have also shown impaired impulse control such as
overspending Overspending is spending more money than one can afford. It is a common problem when easy credit is available. The term overspending is also used for investment projects when payments exceed actual calculated cost. Causes Some overspending is a f ...
, hypersexuality and gambling.


See also

* Dopamine antagonist * Dopamine reuptake inhibitor * Receptor
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
*
GABA receptor agonist A GABA receptor agonist is a drug that is an agonist for one or more of the GABA receptors, producing typically sedative effects, and may also cause other effects such as anxiolytic, anticonvulsant, and muscle relaxant effects. There are three rece ...
*
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 d ...
* Serotonin agonist *
Adrenergic agonist An adrenergic agonist is a drug that stimulates a response from the adrenergic receptors. The five main categories of adrenergic receptors are: α1, α2, β1, β2, and β3, although there are more subtypes, and agonists vary in specificity between ...
(
sympathomimetic Sympathomimetic drugs (also known as adrenergic drugs and adrenergic amines) are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in hea ...
) * Parasympathomimetic drug (acetylcholine agonist) *
Histamine agonist A histamine agonist is a drug which causes increased activity at one or more of the four histamine receptor subtypes. H2: Betazole and Impromidine are examples of agonists used in diagnostics to increase histamine. H3: Betahistine is a weak Hi ...


References


Further reading

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External links

* {{Euphoriants