Novel Serotonin-3 Receptor Antagonists

A structurally novel series of serotonin-3 (5-HT₃) receptor antagonists is described. A computer pharmacophore model for ligands binding to this receptor has been developed and utilized to explain observed structure-activity relationships as well as demonstrated predictive utility. A novel azabicyclic 5-HT₃ receptor ligand prototype [2-(4-amino-5-chloro-2-methoxybenzamidomethyl)-1-azabicyclo[2.2.2]oct-2-ene] has also been discovered, and its selective synthesis, which proceeds through a thermodynamically disfavored allylic azide, is described. 1. Introduction 2. Biological Assays - Definitions 3. Discovery of the Lead Structure 7 (3-[2-(Guanidinomethyl)-1,3-thiazol-4-yl]indole) and Approach to Its Modification 4. Definition and Application of an Initial Computer Pharmacophore Model for Selective 5-HT₃ Receptor Ligands 5. Structure - Activity Relationship (SAR) Studies 6. Synthesis of a Novel Azabicyclic Prototype 7. Summary