Tag: 5-HT6

Introduction

The 5HT6 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 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, 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.

Function

Blockade of central 5-HT₆ receptors has been shown to increase glutamatergic and cholinergic 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.

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, 5-HT₆ 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. However, phase III trials of latrepirdine, idalopirdine, and intepirdine have failed to demonstrate efficacy.

5HT6 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.

As a Drug Target for Agonists

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, indirect 5HT6 activation may play a role in the therapeutic benefits of serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).

Ligands

A large number of selective 5HT6 ligands have now been developed.

Agonists

• Full Agonists:
  • 2-Ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT)
  • WAY-181,187
  • WAY-208,466
  • N-(inden-5-yl)imidazothiazole-5-sulfonamide (43): K_i = 4.5nM, EC₅₀ = 0.9nM, E_max = 98%
  • E-6837 – Full agonist at human 5-HT₆ 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 – 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 – mixed 5-HT₆ / 5-HT₇ antagonist
• Idalopirdine (Lu AE58054) – selective
• Intepirdine (SB-742,457/RVT-101) – selective antagonist
• Landipirdine (RO-5025181, SYN-120)
• Latrepirdine and analogues
• MS-245
• PRX-07034
• SB-258,585
• SB-271,046
• SB-357,134
• SB-399,885
• SGS 518 Fb: [445441-26-9]
• Ro 04-6790
• Ro-4368554
• Atypical antipsychotics (sertindole, olanzapine, asenapine, clozapine)
• WAY-255315 / SAM-315: K_i = 1.1 nM, IC₅₀ = 13 nM
• Rosa rugosa extract

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