Three-dimensional pharmacophore hypotheses for the locust neuronal octopamine receptor (OAR3): 1. Antagonists

Three-dimensional pharmacophore hypotheses were built from a set of 17 mianserin-like antagonists against octopamine receptor class 3 (OAR3) in locust nervous tissue. Among the ten chemical-featured models generated by program Catalyst/Hypo, three hypotheses were considered to be important and predictive in evaluating OAR3 antagonists. Predictions were fairly precise for all molecules but the three outliners including eresepine, metoclopramide and yohimbine. While the ideal and null hypotheses had a cost of 66.50 and 124.97, respectively, the ten resulting hypotheses possessed costs from 78.96 to 92.04. The best hypothesis that was confirmed to have a 95% chance of true correlation yielded a low RMS of 1.05 and high regression r of 0.934. Active antagonists mapped well onto all the features of the hypothesis such as hydrophobic, aromatic ring or positive ionizable features. On the other hand, inactive compounds lack of binding affinity were shown to be poorly capable of achieving an energetically favorable conformation shared by the active molecules in order to fit the 3D chemical feature pharmacophore models. In addition, from the comparison and conformation analysis it was proposed that positive ionizable feature contained a lower weight than hydrophobic or an aromatic ring one. Further research on the comparison of models from agonists and antagonists may help elucidate the mechanisms of OAR3 and other types of octopamine receptor-ligand interactions.