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 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. ''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 5HT₆ 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 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 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 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 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 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. 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 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 5HT₆ 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 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 wer ...

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) * WAY-181,187 *

* ''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 o ...

- 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 o ...

- 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 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 5HT₆ / 5HT₇ 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 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 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, asenapine, clozapine) * WAY-255315 / SAM-315: K_i = 1.1 nM, IC₅₀ = 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 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 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