Discovery of N₁-(6-Chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine as a Potent, Selective, and Orally Active 5-HT₆Receptor Agonist

Abstract

N1-Arylsulfonyltryptamines have been identified as 5-HT6 receptor ligands. In particular, N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-HT6 Ki = 2 nM, EC50 = 6.5 nM, Emax = 95.5%). Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders.

Therapeutic Potential of 5-HT6 Receptor Agonists

“…71−73 Interestingly the same 5-HT 6 R agonists (5,12,20) induced anxiolytic-like effects following systemic or local administration in different rat models. 55,34,71,72,74 Moreover, in some of these studies, the antidepressant-like or anxiolytic-like effects of 5-HT 6 R agonists were reversed by selective 5-HT 6 R antagonists, which confirms the involvement of 5-HT 6 R in the modulation of such processes. Recent outcomes from the works of Nikiforuk 75 indicate that there are different neurochemical mechanisms underlying the anxiolytic-like effects associated with, on the one hand, 5-HT 6 R antagonists (featuring contributions of the GABA A /benzodiazepine system) and, on the other hand, 5-HT 6 R agonists (no identification of the system involved).…”

Schedule-induced polydipsia as a model of compulsive behavior: neuropharmacological and neuroendocrine bases

“…Administration of 5-HT 2C receptor agonists such as the novel and selective agonist WAY163909 induced a dose-dependent decrease in SIP drinking behavior (Martin et al 1998;Rosenzweig-Lipson et al 2007); the 5-HT 2C/2B receptor antagonist SB206553 and SB 200646A and the 5-HT 2C selective receptor antagonist SB242084 abolished this effect and also strongly increased SIP drinking, while the 5HT 2B selective receptor antagonist SB2155505 did not reverse the reduction in SIP (Martin et al 2002;Rosenzweig-Lipson et al 2007). The novel and selective 5-HT 6 receptor agonists, such as WAY18187, proposed for treatment of anxiety and depressive disorders, have been shown effectively to decrease compulsive drinking in SIP in a dose-dependent manner (Bernotas et al 2009;Cole et al 2007;Schechter et al 2008). Serotonergic drugs reduce SIP, as well as combined serotonergic/noradrenergic re-uptake inhibitors such as desipramine and besipirdine (Woods et al 1993;WoodsKettleberger et al 1996).…”

The Serotonin-6 Receptor as a Novel Therapeutic Target

“…E-6801and E-6837 are potent partial agonists of the 5-HT 6 R [45]. Thus, there are few 5-HT 6 R agonists, and only WAY-181187 (displays 50-fold selectivity against serotonergic and other receptors) has been characterized and widely used [46, 47]. Recently, a new 5-HT 6 R agonist, ST1936, has been reported and compared with the characteristics of WAY-181187 [48].…”