5-HT6 receptor

The 5-HT6 receptor is a subtype of is_associated_with::5-HT receptor that binds the is_associated_with::endogenous is_associated_with::neurotransmitter is_associated_with::serotonin (5-hydroxytryptamine, 5-HT). It is a is_associated_with::G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory is_associated_with::neurotransmission. HTR6 denotes the is_associated_with::human is_associated_with::gene encoding for the receptor.

Distribution
The 5-HT6 receptor is expressed almost exclusively in the is_associated_with::brain. It is distributed in various areas including, but not limited to, the is_associated_with::olfactory tubercle, is_associated_with::cerebral cortex (frontal and entorhinal regions), is_associated_with::nucleus accumbens, is_associated_with::striatum, is_associated_with::caudate nucleus, is_associated_with::hippocampus, and the molecular layer of the is_associated_with::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 is_associated_with::motor control, is_associated_with::emotionality, is_associated_with::cognition, and is_associated_with::memory.

Function
Blockade of central 5-HT6 receptors has been shown to increase is_associated_with::glutamatergic and is_associated_with::cholinergic neurotransmission in various brain areas,   whereas activation enhances is_associated_with::GABAergic signaling in a widespread manner. Antagonism of 5-HT6 receptors also facilitates is_associated_with::dopamine and is_associated_with::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 is_associated_with::latrepirdine, is_associated_with::idalopirdine (Lu AE58054), and is_associated_with::SB-742,457 are being developed as novel treatments for is_associated_with::Alzheimer's disease and other forms of is_associated_with::dementia. 5-HT6 antagonists have also been shown to reduce is_associated_with::appetite and produce is_associated_with::weight loss, and as a result, is_associated_with::PRX-07034, is_associated_with::BVT-5,182, and is_associated_with::BVT-74,316 are being investigated for the treatment of is_associated_with::obesity.

Recently, the 5-HT6 agonists is_associated_with::WAY-181,187 and is_associated_with::WAY-208,466 have been demonstrated to be active in rodent models of depression, is_associated_with::anxiety, and is_associated_with::obsessive-compulsive disorder (OCD), and such agents may be useful treatments for these conditions. Additionally, indirect 5-HT6 activation may play a role in the therapeutic benefits of is_associated_with::serotonergic is_associated_with::antidepressants like the is_associated_with::selective serotonin reuptake inhibitors (SSRIs) and is_associated_with::tricyclic antidepressants (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

 * is_associated_with::EMD-386,088 - potent and selective 5HT6 agonist (EC50 1nM)
 * is_associated_with::2-Ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT)
 * is_associated_with::WAY-181,187
 * is_associated_with::WAY-208,466
 * 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%
 * is_associated_with::E-6837 - Full agonist at human 5-HT6 receptors

Partial Agonists

 * is_associated_with::E-6801
 * is_associated_with::E-6837 - partial agonist at rat 5-HT6 receptors. Orally active in rats, and caused weight loss with chronic administration
 * is_associated_with::LSD - Emax = 60%

Antagonists

 * BVT-5182
 * BVT-74316
 * is_associated_with::Cerlapirdine
 * is_associated_with::EGIS-12233 - mixed 5-HT6 / 5-HT7 antagonist
 * is_associated_with::Idalopirdine (Lu AE58054) - selective
 * is_associated_with::Latrepirdine (non-selective) and analogues
 * is_associated_with::MS-245
 * is_associated_with::PRX-07034
 * is_associated_with::SB-258,585
 * is_associated_with::SB-271,046
 * is_associated_with::SB-357,134
 * is_associated_with::SB-399,885
 * is_associated_with::SB-742,457
 * is_associated_with::Ro04-6790
 * is_associated_with::Atypical antipsychotics (is_associated_with::olanzapine, is_associated_with::asenapine, is_associated_with::clozapine)
 * WAY-255315 / SAM-315: Ki = 1.1 nM, IC50 = 13 nM

Genetics
Polymorphisms in the HTR6 gene are associated with is_associated_with::neuropsychiatric disorders. For example an association between the is_associated_with::C267T (is_associated_with::rs1805054) polymorphism and is_associated_with::Alzheimer's disease has been shown. Others have studied the polymorphism in relation to is_associated_with::Parkinson's disease.