Optimization of a pharmacophore model for 5-HT4 agonists using CoMFA and receptor based alignments

Twenty two 5-HT₄ agonists obtained from our laboratory and the recent literature were used to develop a CoMFA model to predict 5-HT₄ agonist activity. Two models were produced and compared for predictivity, the first by alignments based on atom overlapping (model A) and the second by adding agonist binding site interacting points of the 5-HT₄ receptor (model B). Comparison of the two models showed that the q² value for model A was 0.564 vs. 0.582 for model B. Model B indicated that the predictive power model stems from far lower steric contributions, 0.270 compared to model A's 0.502. The dominant defining features were the electrostatic contributions for model B, 0.664 up from 0.477 in model A. The contributions from the LogP factor were minimal, 0.085 in both models. The synthesized compounds showed agonist activity at μmol level.