The 5HT
6 receptor is a subtype of
5HT receptor
5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neur ...
that binds the
endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
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 ...
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
(5-hydroxytryptamine, 5HT).
It is a
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
(GPCR) that is coupled to
Gs and mediates
excitatory
In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the ...
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), ...
.
''HTR6'' denotes the
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, ...
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
encoding for the
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
.
Distribution
The 5HT
6 receptor is expressed almost exclusively in the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
.
It is distributed in various areas including, but not limited to, the
olfactory tubercle
The olfactory tubercle (OT), also known as the tuberculum olfactorium, is a multi-sensory processing center that is contained within the olfactory cortex and ventral striatum and plays a role in reward cognition. The OT has also been shown to ...
,
cerebral cortex
The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of ...
(
frontal
Front may refer to:
Arts, entertainment, and media Films
* ''The Front'' (1943 film), a 1943 Soviet drama film
* ''The Front'', 1976 film
Music
*The Front (band), an American rock band signed to Columbia Records and active in the 1980s and ea ...
and
entorhinal
The entorhinal cortex (EC) is an area of the brain's allocortex, located in the medial temporal lobe, whose functions include being a widespread network hub for memory, navigation, and the perception of time.Integrating time from experience in the ...
regions),
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 hypotha ...
,
striatum
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
,
caudate nucleus
The caudate nucleus is one of the structures that make up the corpus striatum, which is a component of the basal ganglia in the human brain. While the caudate nucleus has long been associated with motor processes due to its role in Parkinson's di ...
,
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, a ...
, and the molecular layer of the
cerebellum
The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...
.
Based on its abundance in
extrapyramidal,
limbic
The limbic system, also known as the paleomammalian cortex, is a set of brain structures located on both sides of the thalamus, immediately beneath the medial temporal lobe of the cerebrum primarily in the forebrain.Schacter, Daniel L. 2012. ''Ps ...
, and
cortical regions it can be suggested that the 5HT
6 receptor plays a role in functions like
motor control
Motor control is the regulation of movement in organisms that possess a nervous system. Motor control includes reflexes as well as directed movement.
To control movement, the nervous system must integrate multimodal sensory information (both f ...
,
emotionality
Emotionality is the observable behavioral and physiological component of emotion. It is a measure of a person's emotional reactivity to a stimulus. Most of these responses can be observed by other people, while some emotional responses can only b ...
,
cognition
Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
, and
memory
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered, ...
.
Function
Blockade of central 5HT
6 receptors has been shown to increase
glutamatergic
Glutamatergic means "related to glutamate". A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/ aspartate) system in the body or brain. Examples include excitatory amino acid receptor agonist ...
and
cholinergic
Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word "choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation. F ...
neurotransmission in various brain areas,
whereas activation enhances
GABAergic
In molecular biology and physiology, something is GABAergic or GABAnergic if it pertains to or affects the neurotransmitter GABA. For example, a synapse is GABAergic if it uses GABA as its neurotransmitter, and a GABAergic neuron produces GABA. A ...
signaling in a widespread manner.
Antagonism of 5HT
6 receptors also facilitates
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 ...
and
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'', ...
release in the frontal cortex,
while stimulation has the opposite effect.
As a drug target for antagonists
Despite the 5HT
6 receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity.
In parallel with this, 5HT
6 antagonists are hypothesized to improve cognition, learning, and memory.
Agents such as
latrepirdine
Latrepirdine (INN, also known as dimebolin and sold as Dimebon) is an antihistamine drug which has been used clinically in Russia since 1983.
Research was conducted in both Russia and western nations into potential applications as a neuroprotect ...
,
idalopirdine
Idalopirdine (INN) (code names Lu AE58054,) is a potent and selective 5-HT6 receptor antagonist under development by Lundbeck as an augmentation therapy for the treatment of cognitive deficits associated with Alzheimer's disease and schizop ...
(Lu AE58054), and
intepirdine
Intepirdine (INN; developmental codes SB-742457, RVT-101) is a selective 5-HT6 receptor antagonist with potential cognition, memory, and learning-enhancing effects. It was under development by GlaxoSmithKline for the treatment of Alzheimer's di ...
(SB-742,457/RVT-101) were evaluated as novel treatments for
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
and other forms of
dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
.
However, phase III trials of latrepirdine, idalopirdine, and intepirdine have failed to demonstrate efficacy.
5HT
6 antagonists have also been shown to reduce
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 regu ...
and produce
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 conn ...
, and as a result,
PRX-07034, BVT-5,182, and BVT-74,316 are being investigated for 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 we ...
.
As a drug target for agonists
Recently, the 5HT
6 agonists
WAY-181,187 and
WAY-208,466
WAY-208466 is a potent and highly selective full agonist of the 5-HT6 receptor. It increases GABA levels in the cerebral cortex and tolerance does not appear to occur to this action upon chronic administration. Animal studies have shown that ...
have been demonstrated to be active in rodent models of
depression,
anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
, and
obsessive-compulsive disorder (OCD), and such agents may be useful treatments for these conditions.
Additionally, indirect 5HT
6 activation may play a role in the therapeutic benefits of
serotonergic
Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse is serotonergic if it uses serotonin as its neurotransmitter. A serotonergic neuron ''produces'' serotonin. A substance is ...
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, hea ...
s like 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 extracell ...
s (SSRIs) and
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 wer ...
s (TCAs).
Ligands
A large number of selective 5HT
6 ligands have now been developed.
Agonists
Full agonists
*
2-Ethyl-5-methoxy-N,N-dimethyltryptamine
2-Ethyl-5-methoxy-''N'',''N''-dimethyltryptamine (EMDT) is a tryptamine derivative which is used in scientific research. It acts as a selective 5-HT6 receptor agonist, with a Ki of 16 nM, and was one of the first selective agonists developed ...
(EMDT)
*
WAY-181,187
*
WAY-208,466
WAY-208466 is a potent and highly selective full agonist of the 5-HT6 receptor. It increases GABA levels in the cerebral cortex and tolerance does not appear to occur to this action upon chronic administration. Animal studies have shown that ...
* ''N''-(inden-5-yl)imidazothiazole-5-sulfonamide (43): ''K''
i = 4.5nM, EC
50 = 0.9nM, E
max = 98%
*
E-6837
E-6837 is an orally active, 5-HT6 agonist developed in an attempt to create an anti-obesity medication. In cell lines expressing rat 5-HT6 receptors, it acted as a partial agonist (on presumed silent receptors), while it acted as a full agonist o ...
- Full agonist at human 5HT
6 receptors
Partial agonists
*
E-6801
E-6801 is a partial agonist of the 5-HT6 receptor. It enhanced recognition memory and reversed the memory deficits of scopolamine in an object recognition task in a rat model. The mechanism of memory enhancement is due to a combined modulation o ...
*
E-6837
E-6837 is an orally active, 5-HT6 agonist developed in an attempt to create an anti-obesity medication. In cell lines expressing rat 5-HT6 receptors, it acted as a partial agonist (on presumed silent receptors), while it acted as a full agonist o ...
- partial agonist at rat 5-HT
6 receptors. Orally active in rats, and caused weight loss with chronic administration
*
EMD-386,088
EMD-386088 is an indole derivative which is used in scientific research. It acts as a potent 5-HT6 receptor partial agonist, with a Ki of 1 nM, a significantly higher affinity than older 5-HT6 agonists such as EMDT, although it possesses moder ...
- potent partial agonist (EC
50 = 1 nM) but non-selective
*
LSD
Lysergic acid diethylamide (LSD), also known colloquially as acid, is a potent psychedelic drug. Effects typically include intensified thoughts, emotions, and sensory perception. At sufficiently high dosages LSD manifests primarily mental, vi ...
- E
max = 60%
Antagonists and inverse agonists
* ALX-1161
*
AVN-211
AVN-211 (CD-008-0173) is a drug which acts as a highly selective 5-HT6 receptor antagonist and is under development by Avineuro Pharmaceuticals for the treatment of schizophrenia. In early 2011, it successfully completed phase IIa clinical tr ...
* BVT-5182
* BVT-74316
*
Cerlapirdine
Cerlapirdine (USAN; SAM-531, WAY-262,531, PF-05212365) is a drug which was under development by Wyeth/Pfizer for the treatment of cognitive disorders associated with Alzheimer's disease and schizophrenia. In a phase II clinical trial it demons ...
- selective
*
EGIS-12233
EGIS-12,233 is a drug with applications in scientific research, acting as a potent and selective antagonist for both the 5-HT6 and 5-HT7 serotonin receptor subtypes, with good selectivity over other receptors. It has been shown to increase do ...
- mixed 5HT
6 / 5HT
7 antagonist
*
Idalopirdine
Idalopirdine (INN) (code names Lu AE58054,) is a potent and selective 5-HT6 receptor antagonist under development by Lundbeck as an augmentation therapy for the treatment of cognitive deficits associated with Alzheimer's disease and schizop ...
(Lu AE58054) - selective
*
Intepirdine
Intepirdine (INN; developmental codes SB-742457, RVT-101) is a selective 5-HT6 receptor antagonist with potential cognition, memory, and learning-enhancing effects. It was under development by GlaxoSmithKline for the treatment of Alzheimer's di ...
(SB-742,457/RVT-101) - selective
antagonist
An antagonist is a character in a story who is presented as the chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
*
Landipirdine (RO-5025181, SYN-120)
*
Latrepirdine
Latrepirdine (INN, also known as dimebolin and sold as Dimebon) is an antihistamine drug which has been used clinically in Russia since 1983.
Research was conducted in both Russia and western nations into potential applications as a neuroprotect ...
(non-selective) and analogues
*
MS-245
MS-245 is a tryptamine derivative used in scientific research. It acts as a selective 5-HT6 receptor antagonist with a Ki of 2.3 nM, and was derived through structure-activity relationship development of the selective 5-HT6 agonist EMDT. It ...
*
PRX-07034
*
SB-258,585
*
SB-271,046
SB-271046 is a drug which is used in scientific research. It was one of the first selective 5-HT6 receptor antagonists to be discovered, and was found through high-throughput screening of the SmithKline Beecham Compound Bank using cloned 5-HT6 r ...
*
SB-357,134
*
SB-399,885
SB-399885 is a drug which is used in scientific research. It acts as a potent, selective and orally active 5-HT6 receptor antagonist, with a Ki of 9.0nM. SB-399885 and other 5-HT6 antagonists show nootropic effects in animal studies, as well a ...
*
SGS 518 SGS may refer to:
Acronym usage
* ISO 639-3 code for the Samogitian dialect
* ISO 3166 trigram for South Georgia and the South Sandwich Islands
* FAA location identifier for South St. Paul Municipal Airport
Companies and organizations
* SGS Esse ...
Fb:
45441-26-9*
Ro 04-6790
* Ro-4368554
*
Atypical antipsychotics
The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilizers and ne ...
(
sertindole
Sertindole, sold under the brand name Serdolect among others, is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company Lundbeck and marketed under license by Abbott Labs. Like other atypical antipsychotics, i ...
,
olanzapine
Olanzapine (sold under the trade name Zyprexa among others) is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is ta ...
,
asenapine
Asenapine, sold under the brand name Saphris among others, is an atypical antipsychotic medication used to treat schizophrenia and acute mania associated with bipolar disorder.
It was chemically derived via altering the chemical structure of the ...
,
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 respo ...
)
* WAY-255315 / SAM-315: K
i = 1.1 nM, IC
50 = 13 nM
*
Rosa rugosa
''Rosa rugosa'' (rugosa rose, beach rose, Japanese rose, Ramanas rose, or letchberry) is a species of rose native to eastern Asia, in northeastern China, Japan, Korea and southeastern Siberia, where it grows on beach coasts, often on sand dunes. ...
extract
Genetics
Polymorphisms in the HTR6 gene are associated with
neuropsychiatric disorder
A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitti ...
s. For example, an association between the
C267T
In genetics, Rs1805054, also called C267T, is a name used for a specific genetic variation, a single nucleotide polymorphism (SNP), in the HTR6 gene.
It is one of the few investigated polymorphisms of its gene.
C267T is a synonymous polymorphism.
...
(
rs1805054) polymorphism and
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
has been shown.
Others have studied the polymorphism in relation to
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 ...
.
See also
*
5-HT receptor
5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neur ...
*
5-HT1 receptor
*
5-HT2 receptor
*
5-HT3 receptor
*
5-HT4 receptor
*
5-HT5 receptor
References
Further reading
*
*
*
*
*
*
*
*
*
*
*
*
*
External links
*
*
*
{{DEFAULTSORT:5-HT6 Receptor
Serotonin receptors