Novel Agonists of 5HT_2C Receptors. Synthesis and Biological Evaluation of Substituted 2-(Indol-1-yl)-1-methylethylamines and 2-(Indeno[1,2-b]pyrrol-1-yl)-1-methylethylamines. Improved Therapeutics for Obsessive Compulsive Disorder

Abstract

The syntheses of a series of substituted 2-(indol-1-yl)-1-methylethylamines and 2-(indeno[1,2- b]pyrrol-1-yl)-1-methylethylamines are reported. The binding affinities of the compounds at 5HT2C and 5HT2A receptors (79% homology in the transmembrane domain) were determined. The ligands displayed selectivity for 5HT2C receptors relative to 5HT2A receptors. Compounds were functionally characterized both in vitro and in vivo as 5HT2C receptor agonists. 5f, 5l, 5n, 5o, 5q, 14c, 14f, 14k, and 14m exhibited anticompulsive activity in an animal model of obsessive compulsive disorder.

5-HT 2C receptors are involved in the discriminative stimulus effects of citalopram in rats

“…Thus, Ro60-0175, which acts as a potent and preferential agonist at 5-HT 2C receptors (Bös et al 1997;Millan et al 1997;Martin et al 1998), fully generalized to citalo- …”

“…Ro60-0175 shows negligible affinity for other sites, including 5-HT 2A receptors, with the exception of 5-HT 2B receptors. However, it is a partial agonist at these sites (Bös et al 1997;Martin et al 1998), which are present in only a low density in the CNS and which remain of uncertain functional significance (Duxon et al 1997). Further, the citalopram DS was abolished by the highly selective 5-HT 2C antagonist, SB242,084, which shows only 100-fold lower affinity for 5-HT 2B receptors (Kennett et al 1997).…”

“…Herein, employing Ro60-0175 and SB242,084, novel and selective agonist and antagonist at 5-HT 2C receptors, respectively (Bös et al 1997;Kennett et al 1997;Millan et al 1997), we evaluated their potential role in the DS properties of citalopram.…”

Identification of structural determinants of ligand selectivity in 5-HT2 receptor subtypes on the basis of protein–ligand interactions

“…The biological functions of mCPP and MK212, which have an arylpiperazine moiety, have been thoroughly investigated and reported as selective 5-HT 2C agonists [64,65]. Ro 60-0175 is also known to be a 5-HT 2C agonist, and displayed selectivity over 5-HT 2B [66]. Org 37684 is a 5-HT 2C agonist, and exhibits moderate selectivity over other 5-HT 2 receptor subtypes [67].…”

New directions for erectile dysfunction therapies

“…53 They both induce erection in rodents, but they also significantly inhibit ejaculation and sexual behavior. 2 Several agonists with selective action on 5-HT 2C receptors have been synthetized 59 and shown to induce penile erection in rats, suggesting an important role for the 5-HT 2C receptor in the control of erectile mechanisms. Further supporting this, RSD 992, an agonist at 5-HT 2C receptors, induced erections and facilitated male copulative behavior.…”