The 5HT₆ 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 (GPCR) that is coupled to G_s and mediates excitatory neurotransmission. ''HTR6'' denotes the human gene encoding for the receptor.

Distribution

The 5HT₆ receptor is expressed almost exclusively in the brain. It is distributed in various areas including, but not limited to, the olfactory tubercle, cerebral cortex ( frontal and entorhinal regions), nucleus accumbens,

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, hippocampus, 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, and cortical regions it can be suggested that the 5HT₆ 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,

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.

Function

Blockade of central 5HT₆ receptors has been shown to increase glutamatergic and cholinergic 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 5HT₆ 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 release in the frontal cortex, while stimulation has the opposite effect.

As a drug target for antagonists

Despite the 5HT₆ 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, 5HT₆ antagonists are hypothesized to improve cognition, learning, and memory. Agents such as latrepirdine, idalopirdine (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. However, phase III trials of latrepirdine, idalopirdine, and intepirdine have failed to demonstrate efficacy. 5HT₆ 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, and as a result,

PRX-07034 PRX-07034 is a selective 5-HT6 receptor antagonist. It has cognition and memory-enhancing properties and potently decreases food intake and body weight in rodents. PRX-07034 was under development by Epix Pharmaceuticals for the treatment of ...

, BVT-5,182, and BVT-74,316 are being investigated for the treatment of obesity.

As a drug target for agonists

Recently, the 5HT₆ agonists

WAY-181,187 WAY-181187 is a high affinity and selective 5-HT6 receptor full agonist. It induces robust increases in extracellular GABA levels in the frontal cortex, hippocampus, striatum, and amygdala of rats without affecting concentrations in the nucleu ...

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, and obsessive-compulsive disorder (OCD), and such agents may be useful treatments for these conditions. Additionally, indirect 5HT₆ activation may play a role in the therapeutic benefits of serotonergic

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 inhibitors (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 we ...

s (TCAs).

Ligands

A large number of selective 5HT₆ 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) *

* ''N''-(inden-5-yl)imidazothiazole-5-sulfonamide (43): ''K''_i = 4.5nM, EC₅₀ = 0.9nM, E_max = 98% * E-6837 - Full agonist at human 5HT₆ receptors

Partial agonists

* E-6801 * E-6837 - partial agonist at rat 5-HT₆ 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 (EC₅₀ = 1 nM) but non-selective * LSD - E_max = 60%

Antagonists and inverse agonists

* ALX-1161 * AVN-211 * BVT-5182 * BVT-74316 * Cerlapirdine - 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 5HT₆ / 5HT₇ antagonist * Idalopirdine (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 (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 ...

SB-258,585 SB-258585 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 8.9nM. It is used in its 125I radiolabelled form to map the distribution of 5-HT6 receptors in t ...

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-357134 is a drug which is used in scientific research. It acts as a potent, selective and orally active 5-HT6 receptor antagonist. SB-357134 and other 5-HT6 antagonists show nootropic effects in animal studies, and have been proposed as pote ...

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 Fb: 45441-26-9*

Ro 04-6790 Ro 04-6790 is a drug, developed by Hoffmann–La Roche, which has applications in scientific research. It acts as a potent and selective receptor antagonist for the 5-HT6 serotonin receptor subtype, with little or no affinity at other receptor ...

* Ro-4368554 * Atypical antipsychotics ( sertindole, olanzapine, asenapine, clozapine) * WAY-255315 / SAM-315: K_i = 1.1 nM, IC₅₀ = 13 nM * Rosa rugosa extract

Genetics

Polymorphisms in the HTR6 gene are associated with neuropsychiatric disorders. 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 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. ...

) polymorphism and

has been shown. Others have studied the polymorphism in relation to Parkinson's disease.

References

External links

* * * {{DEFAULTSORT:5-HT6 Receptor Serotonin receptors