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, ...

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 ...

serotonin (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 G_s 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 b ...

encoding for the receptor.

Distribution

The 5HT₆ receptor is expressed almost exclusively in the

brain The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...

. 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 o ...

( frontal and entorhinal 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 hypot ...

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 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, ...

, 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 cere ...

. 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, thoug ...

, 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 5HT₆ 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 agonist, excitato ...

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. ...

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 chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...

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 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 (SB-742,457/RVT-101) were evaluated as novel treatments for Alzheimer's disease 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. 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 reg ...

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 con ...

, 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 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 ...

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 potency (pharmacology), potent and highly binding selectivity, selective full agonist of the 5-HT6 receptor, 5-HT6 receptor. It increases GABA levels in the cerebral cortex and drug tolerance, tolerance does not appear to occur to ...

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 Turmoil may refer to: * ''Turmoil'' (1984 video game), a 1984 video game released by Bug-Byte * ''Turmoil'' (2016 video game), a 2016 indie oil tycoon video ...

, 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 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 ...

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 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 extracellul ...

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 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 (EMDT) *

* ''N''-(inden-5-yl)imidazothiazole-5-sulfonamide (43): ''K''_i = 4.5nM, EC₅₀ = 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 ...

- Full agonist at human 5HT₆ 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 of ...

- partial agonist at rat 5-HT₆ receptors. Orally active in rats, and caused weight loss with chronic administration * EMD-386,088 - 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 ...

- mixed 5HT₆ / 5HT₇ antagonist * Idalopirdine (Lu AE58054) - selective * Intepirdine (SB-742,457/RVT-101) - selective antagonist * Landipirdine (RO-5025181, SYN-120) * Latrepirdine (non-selective) and analogues * MS-245 *

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-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 * 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 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 ...

) * 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 (

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 Alzheimer's disease 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 ...

References

External links

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