Molecular modeling of 5-HT3 receptor ligands.

Ligands of various chemical classes (e.g., indoles, indazoles, benzamides, carbazoles, and quinolines) have demonstrated high affinity for the 5-HT₃ receptor in radiolabeled ligand-binding studies, and have shown 5-HT₃ receptor antagonistic activity in functional assays which utilize the excitatory effects of 5-HT on enteric neurons and autonomic afferents. Several 5-HT₃ antagonists are currently being evaluated for potential use in the treatment of migraine, schizophrenia, and anxiety, and a few have already demonstrated high efficacy as antiemetics in cancer chemotherapy. The purpose of this presentation is to highlight the significant structure-affinity relationships (SAFIR) and common geometrical features among 5-HT₃ receptor ligands, and to describe the three-dimensional pharmacophore for the 5-HT₃ recognition site derived from computational techniques. The chemical template containing the recognition elements (functional groups) for the 5-HT₃ receptor are: an aromatic or heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center, interrelated by well-defined distances. Two “binding shapes” or “active shapes” for 5-HT₃ ligands have been identified from detailed conformational analyses.