Molecular modeling on platelet-activating factor (PAF) and new proposed PAF antagonists

Platelet-activating factor (PAF) is an autacoid derived from cellular membrane phospholipids in response to chemical or physical stimuli. It has been identified as 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphocholine; the alkyl group is composed of 16 or 18 carbon atoms in human cells. PAF can cause a series of pathophysiological effects, related to inflammatory and allergic diseases such as asthma, gastric ulcerations, transplant rejections, psoriasis, cerebral, renal, and myocardial ischemia. As PAF biological action is a result of interactions with specific receptors on target cells, several specific PAF receptor antagonists have been proposed for therapeutic control of the pathological states in which PAF is implicated. In this work we have calculated at AMI level 16 conformations of a model (alkyl = octyl) of (R)-PAF. We have used these conformations and calculated structures of two hetrazepines (WEB 2086 and E 6123), FR 128998 and RP 59227, known antagonists of PAF activity currently under development, to test a recently proposed pharmacophore map. Our results suggest that the model is too rigid. Having mind, we used the pharmacophore model to evaluate the potential activity of a new series of proposed PAF receptor antagonists based on bicyclo[3.3.0]-2-oxaoctane. The results were used to decide which compounds should receive priority in synthesis. The synthetic results and pharmacological profiles of the new derivatives will be published elsewhere. (C) 1996 John Wiley & Sons, Inc.