Novel 1-(arylsulfonyl)-3-(piperidinylmethyl)-1H-indoles as potent and selective 5-HT6 antagonists

Abstract

The 5-HT6 serotonin receptor subtype is one of the seven major types of serotonin receptors (5-HT1-5-HT7). This receptor is a member of the seven-transmembrane-spanning G-protein-coupled receptor family that is pos. coupled to adenylate cyclase. The potential role of selective 5-HT6 receptor ligands in the treatment of various central nervous system disorders such as depression, anxiety, cognition, and feeding disorders has stimulated a surge of interest in this area. A novel class of 1-(arylsulfonyl)-3-(piperidinylmethyl)-1H-indoles was designed and prepd. as potent and selective 5-HT6 ligands. Among these, compd. 1 showed excellent affinity (Ki = 1 nM) towards the 5-HT6 receptor, and excellent selectivity over 5-HT7 receptor. In addn., compd. 1 is a full antagonist in a 5-HT6 functional assay with superior potency (IC50 = 1.3 nM).