Investigation of 5-HT4 agonist activities using molecular field analysis

Abstract

Determination of the structural properties of the 5-HT₄ agonist binding site is the major aim for developing specific selective agonists. These agonists are of potential therapeutic value for treating irritable bowel syndrome. In an attempt to deduce structural properties of the 5-HT₄ agonist binding site, a pharmacophore model and the molecular structural properties of known agonists have been compared with respect to biological activity. The pharmacophore model was developed using seven known active agonists, indolecarbazimidamide, 3-N-isopropylbenzimidazolone amide, 3-N-ethylbenzimidazolone amide and benzamide, (R)-zacopride, 5-CT and metoclopramide. Extensive study of the X-ray structures of these agonists, or closely-related compounds, identified important interactions constraining the conformational flexibility of the sidechains of the agonists. This knowledge, together with molecular mechanics optimization methods, allowed us to deduce the likely binding conformations of the agonists at the 5-HT₄ agonist binding site. Superimposition of the agonists was carried out using atom-by-atom fit with respect to 5-HT. This alignment was used to develop CoMFA models of the likely 5-HT₄ agonist binding site. The models were highly predictive with cross-validated q² values of 0.26–0.51 and final r ² values of 0.96–0.99. Steric, electrostatic and lipophilic properties of the agonist were all found to be important. The final model identified regions in 3D property space which were important for modulating the activity of agonists.