A Three-Dimensional Pharmacophore Model for 5-Hydroxytryptamine₆(5-HT₆) Receptor Antagonists

Abstract

Forty-five structurally diverse 5-hydroxytryptamine(6) receptor (5-HT(6)R) antagonists were selected to develop a 3D pharmacophore model with the Catalyst software. The structural features for antagonism at this receptor are a positive ionizable atom interacting with Asp(3.32), a hydrogen bond acceptor group interacting with Ser(5.43) and Asn(6.55), a hydrophobic site interacting with residues in a hydrophobic pocket between transmembranes 3, 4, and 5, and an aromatic-ring hydrophobic site interacting with Phe(6.52).

1-[1-(4-Chlorobenzenesulfonyl)-1H-indole-3-yl]-3-[4-(pyridin-2-yl)piperazin-1-yl]propan-1-one

“…A 5-HT 6 antagonist pharmacophore has been previously described in the literature [7]. In our efforts to prepare potent and highly selective antagonists targeting 5-HT 6 based on this reported pharmacophore [8,9], we performed the synthesis of the title compound 1-[1-(4-chlorobenzenesulfonyl)-1H-indole-3-yl]-3-[4-(pyridin-2-yl)piperazin-1-yl]propan-1-one and evaluated its affinity for the 5-HT 6 receptor in a standard binding assay.…”

Synthesis and biological evaluation of novel N1-phenylsulphonyl indole derivatives as potent and selective 5-HT6R ligands for the treatment of cognitive disorders

“…We wished to determine whether introduction of piperazinyl methyl group on N 1 -phenylsulfonyl moiety at C-3 0 position would have a desired effect on the binding to 5-HT 6 R and aimed to investigate the structure-activity relationship (SAR). Researchers have developed a pharmacophore model ( Figure 3) for 5-HT 6 receptor antagonists, based on reported chemically diverse 5-HT 6 receptor antagonists [35][36][37][38][39][40][41][42]34 . In this pharmacophore model, four core features were taken into consideration which include the positive ionizable atom (PI, usually a secondary or tertiary amino group), a hydrogen bond acceptor group (HBA, usually a sulfone or sulfonamide group), a hydrophobic site (HYD) and -electron donor aromatic or heterocyclic ring (AR).…”

Design, synthesis and pharmacological evaluation of indolylsulfonamide amines as potent and selective 5-HT6receptor antagonists

“…Since then a lot of reports have been published regarding variations in N,N-dimethyl amino alkyl side chain on and around the indole nucleus and their affinity 21,32,33 ( Figure 2). Numerous selective antagonists of 5-HT 6 receptors have been disclosed during the last decade [34][35][36][37][38][39][40][41][42] and a pharmacophore model for this type of receptor antagonists has been developed based on known structurally diverse 5-HT 6 receptor antagonists [43][44][45][46][47][48][49] . In general, the model entails the positive ionizable atom (usually a secondary or tertiary amino group), a hydrogen bond acceptor group (usually a sulfone or sulfonamide group), a hydrophobic site (HYD) and -electron donor aromatic or heterocyclic ring (AR).…”