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-phosphocholin e; the alkyl group is composed of 16 or 18 carbon atoms in human cells . PAF can cause a series of pathophysiological effects, related to inf lammatory and allergic diseases such as asthma, gastric ulcerations, t ransplant rejections, psoriasis, cerebral, renal, and myocardial ische mia. As PAF biological action is a result of interactions with specifi c 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 le vel 16 conformations of a model (alkyl = octyl) of (R)-PAF. We have us ed 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 pha rmacophore map. Our results suggest that the model is too rigid. Havin g mind, we used the pharmacophore model to evaluate the potential acti vity of a new series of proposed PAF receptor antagonists based on bic yclo[3.3.0]-2-oxaoctane. The results were used to decide which compoun ds should receive priority in synthesis. The synthetic results and pha rmacological profiles of the new derivatives will be published elsewhe re. (C) 1996 John Wiley & Sons, Inc.