5-HT6 receptor
Encyclopedia
The 5-HT6 receptor is a subtype of 5-HT receptor
that binds the endogenous
neurotransmitter
serotonin
(5-hydroxytryptamine, 5-HT). It is a G protein-coupled receptor
(GPCR) that is coupled to Gs/Go and mediates excitatory neurotransmission
. HTR6 denotes the human
gene
encoding for the receptor
.
. It is distributed in various areas including, but not limited to, the olfactory tubercle
, cerebral cortex
(frontal and entorhinal
regions), nucleus accumbens
, striatum
, caudate nucleus
, hippocampus
, and the molecular layer of the cerebellum
. Based on its abundance in extrapyramidal
, limbic
, and cortical regions it can be suggested that the 5-HT6 receptor plays a role in functions like motor control
, emotionality
, cognition
, and memory
.
neurotransmission in various brain areas, whereas activation enhances GABAergic signaling in a widespread manner. Antagonism of 5-HT6 receptors also facilitates dopamine
and norepinephrine
release in the frontal cortex, while stimulation has the opposite effect.
Despite the 5-HT6 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, 5-HT6 antagonists improve cognition, learning, and memory, and agents such as latrepirdine, Lu AE58054
, and SB-742,457
are being developed as novel treatments for Alzheimer's disease
and other dementia
s. 5-HT6 antagonists have also been shown to reduce appetite
and produce weight loss
, and as a result, PRX-07034
, BVT-5,182, and BVT-74,316 are being investigated for the treatment of obesity
.
Recently, the 5-HT6 agonists WAY-181,187
and WAY-208,466
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, it can be inferred that 5-HT6 activation likely plays a major role in the therapeutic benefits of serotonergic
antidepressant
s like the selective serotonin reuptake inhibitor
s (SSRIs) and tricyclic antidepressant
s (TCAs).
As the protein is a neuroreceptor it is possible that genetic variations in the gene would have an effect on brain,
and research studies have investigated whether polymorphisms
is associated with brain-related variables, such as neuropsychiatric disorders.
For example, in 2004 one Chinese study reported an association between the C267T (rs1805054
) polymorphism and Alzheimer's disease
.
Others have studied the polymorphism in relation to Parkinson's disease
.
5-HT receptor
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...
that binds the endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
(5-hydroxytryptamine, 5-HT). It is a G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
(GPCR) that is coupled to Gs/Go and mediates excitatory neurotransmission
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
. HTR6 denotes the human
Human
Humans are the only living species in the Homo genus...
gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
encoding for the receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
.
Distribution
The 5-HT6 receptor is expressed almost exclusively in the brainBrain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. It is distributed in various areas including, but not limited to, the olfactory tubercle
Olfactory tubercle
The olfactory tubercle is a structure involved in Olfaction.It is present in humans, but much smaller than it is in some other animals.It is a frequent subject of research.-External links:...
, cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
(frontal and entorhinal
Entorhinal cortex
The entorhinal cortex is located in the medial temporal lobe and functions as a hub in a widespread network for memory and navigation. The EC is the main interface between the hippocampus and neocortex...
regions), nucleus accumbens
Nucleus accumbens
The nucleus accumbens , also known as the accumbens nucleus or as the nucleus accumbens septi , is a collection of neurons and forms the main part of the ventral striatum...
, striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
, caudate nucleus
Caudate nucleus
The caudate nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate nucleus is an important part of the brain's learning and memory system.-Anatomy:...
, hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, and the molecular layer of the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
. Based on its abundance in extrapyramidal
Extrapyramidal system
In human anatomy, the extrapyramidal system is a neural network located in the brain that is part of the motor system involved in the coordination of movement. The system is called "extrapyramidal" to distinguish it from the tracts of the motor cortex that reach their targets by traveling through...
, limbic
Limbic system
The limbic system is a set of brain structures including the hippocampus, amygdala, anterior thalamic nuclei, septum, limbic cortex and fornix, which seemingly support a variety of functions including emotion, behavior, long term memory, and olfaction. The term "limbic" comes from the Latin...
, and cortical regions it can be suggested that the 5-HT6 receptor plays a role in functions like motor control
Motor control
Motor control are information processing related activities carried out by the central nervous system that organize the musculoskeletal system to create coordinated movements and skilled actions...
, emotionality
Emotionality
Emotionality is the observable behavioral and physiological component of emotion, and is a measure of a person's emotional reactivity to a stimulus. It is often used by psychology researchers to operationalize emotion in research studies...
, cognition
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
, and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
.
Function
Blockade of central 5-HT6 receptors has been shown to increase glutamatergic and cholinergicCholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...
neurotransmission in various brain areas, whereas activation enhances GABAergic signaling in a widespread manner. Antagonism of 5-HT6 receptors also facilitates dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
release in the frontal cortex, while stimulation has the opposite effect.
Despite the 5-HT6 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, 5-HT6 antagonists improve cognition, learning, and memory, and agents such as latrepirdine, Lu AE58054
Lu AE58054
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 schizophrenia. As of February 2010 it is in phase II clinical trials.- External links :* *...
, and SB-742,457
SB-742,457
SB-742,457 is a selective 5-HT6 receptor antagonist with cognition, memory, and learning-enhancing effects. It is currently under development by GlaxoSmithKline for the treatment of Alzheimer's disease and has demonstrated preliminary efficacy in phase II clinical trials.- References :...
are being developed as novel treatments for Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
and other dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
s. 5-HT6 antagonists have also been shown to reduce appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
and produce weight loss
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
, and as a result, PRX-07034
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...
, BVT-5,182, and BVT-74,316 are being investigated for the treatment of obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
.
Recently, the 5-HT6 agonists WAY-181,187
WAY-181,187
WAY-181,187 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 nucleus accumbens or thalamus, and has modest to no effects...
and WAY-208,466
WAY-208,466
WAY-208,466 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...
have been demonstrated to be active in rodent models of depression, anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, and obsessive-compulsive disorder
Obsessive-compulsive disorder
Obsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
(OCD), and such agents may be useful treatments for these conditions. Additionally, it can be inferred that 5-HT6 activation likely plays a major role in the therapeutic benefits of serotonergic
Serotonergic
Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter...
antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s like the selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s (SSRIs) and tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s (TCAs).
Ligands
A large number of selective 5-HT6 ligands have now been developed and this is a productive current area of research.Full agonists
- EMD-386,088EMD-386,088EMD-386,088 is an indole derivative which is used in scientific research. It acts as a potent and selective 5-HT6 receptor agonist, with a Ki of 1 nM, a significantly higher affinity than older 5-HT6 agonists such as EMDT, although it possesses moderate affinity for the 5-HT3 receptor as well....
- potent and selective 5HT6 agonist (EC50 1nM) - 2-Ethyl-5-methoxy-N,N-dimethyltryptamine2-Ethyl-5-methoxy-N,N-dimethyltryptamine2-Ethyl-5-methoxy-N,N-dimethyltryptamine 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 for this receptor...
(EMDT) - WAY-181,187WAY-181,187WAY-181,187 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 nucleus accumbens or thalamus, and has modest to no effects...
- WAY-208,466WAY-208,466WAY-208,466 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...
- N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (compound 11q)
- N-(inden-5-yl)imidazothiazole-5-sulfonamide (43): Ki = 4.5nM, EC50 = 0.9nM, Emax = 98%
Antagonists
- BVT-5182
- BVT-74316
- CerlapirdineCerlapirdineCerlapirdine is a drug which is under development by Wyeth/Pfizer for the treatment of cognitive disorders associated with Alzheimer's disease and schizophrenia...
- EGIS-12233EGIS-12233EGIS-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 dopamine release in cochlear tissue, suggesting a role for...
- mixed 5-HT6 / 5-HT7 antagonist - Latrepirdine (non-selective) and analogues
- Lu AE58054Lu AE58054Lu 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 schizophrenia. As of February 2010 it is in phase II clinical trials.- External links :* *...
- MS-245MS-245MS-245 is a tryptamine derivative which is 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 has been used as a lead compound for further...
- PRX-07034PRX-07034PRX-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...
- SB-258,585SB-258,585SB-258,585 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...
- SB-271,046SB-271,046SB-271,046 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 receptors as a target, with an initial lead compound...
- SB-357,134SB-357,134SB-357,134 is a drug which is used in scientific research. It acts as a potent, selective and orally active 5-HT6 receptor antagonist. SB-357,134 and other 5-HT6 antagonists show nootropic effects in animal studies, and have been proposed as potential novel treatments for cognitive disorders such...
- SB-399,885SB-399,885SB-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-742,457SB-742,457SB-742,457 is a selective 5-HT6 receptor antagonist with cognition, memory, and learning-enhancing effects. It is currently under development by GlaxoSmithKline for the treatment of Alzheimer's disease and has demonstrated preliminary efficacy in phase II clinical trials.- References :...
- Ro04-6790Ro04-6790Ro04-6790 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 receptors...
- Atypical antipsychotics (olanzapineOlanzapineOlanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
, asenapineAsenapineAsenapine is a new atypical antipsychotic developed for the treatment of schizophrenia and acute mania associated with bipolar disorder by Schering-Plough after its November 19, 2007 merger with Organon International. Development of the drug, through Phase III trials, began while Organon was still...
, clozapineClozapineClozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
) - WAY-255315 / SAM-315: Ki = 1.1nM, IC = 13nM
Genetics
The receptor is encoded by the HTR6 gene.As the protein is a neuroreceptor it is possible that genetic variations in the gene would have an effect on brain,
and research studies have investigated whether polymorphisms
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
is associated with brain-related variables, such as neuropsychiatric disorders.
For example, in 2004 one Chinese study reported an association between the C267T (rs1805054
Rs1805054
In genetics, Rs1805054, also called C267T, is a name used for a specific genetic variation, a single nucleotide polymorphism , 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
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
Others have studied the polymorphism in relation to Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.