A pharmacophore for high affinity PAF antagonists .1. Electronic model using molecular electrostatic potential

PAF is a powerful phospholipid-derived autacoid involved in many physio-pathological mechanisms. Many PAF antagonists have been synthesized and assayed for therapeutic purposes. In this study, molecular electrostatic potential is used to compare the electronic properties of 48 'heterocyclic sp(2) nitrogen' highly potent PAF antagonists, belonging to six series (nine hetrazepines, five pyrrolo[1,2-c]thiazoles, 14 carboxamides, nine dihydropyridines, nine pyridinylthiazolidines and two imidazo[4,5-c]pyridines). Their common features consist of three main electronegative zones (A, B-1 and B-2) describing the electronic pharmacophore of these ligands. The high affinity of these PAF antagonists seems to be related to this electronegative system A-B-x, which is characterized by three distances A-B-1 (9.3 +/- 1.0 Angstrom), A-B-2 (13.4 +/- 0.7 Angstrom) and B-1-B-2 (4.9 +/- 0.9 Angstrom). Moreover, B-1 and B-2 may surround a common anchorage point in the binding site of the receptor.