A 3D-Quantitative Structure-Activity Relationship Study of Benzamide Type Serotonin 5-HT₄ Receptor Agonists Based on a Comparative Molecular Field Analysis Model, and the Design and Synthesis of Potent Agonists

Abstract

A 3D-quantitative structure-activity relationship (3D-QSAR) study was carried out using comparative molecular field analysis (CoMFA) of the 5-HT₄ agonistic activity of benzamide type compounds, which had been already synthesized and reported to show 5-HT₄ agonistic activity. The chosen alignment yielded a good cross-validated result (γ-²_cv=0.628). This CoMFA model was able to predict the 5-HT₄ agonistic activity of three structurally different compounds. Consequently, 5-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-6-chloro-3, 4-dihydo-2H-1-benzopyran-8-carboxamide (22) was obtained as the most potent 5-HT₄ agonist.