Toward a platelet-activating factor pseudoreceptor 2. Three-dimensional semiempirical models for agonist and antagonist binding

Abstract

Platelet-activating factor (PAF) is an autacoid involved in many inflammatory and allergic diseases. The pathophysiologic effects of PAF result from its interaction with specific cellular membrane receptors, and a number of compounds have been synthesized to antagonize the PAF receptor. Improvements on the affinity of the antagonists for the PAF receptor can be expected from the knowledge of their mode of interaction, but this has been hampered by the absence of structural information on the receptor. As an initial step for the construction of a PAF pseudoreceptor, we proposed in a previous paper a series of molecular probes as representatives of the key amino acids of the active site of the PAF receptor. We present now the development of three-dimensional proposals for pseudoreceptors for PAF by semiempirical molecular modeling. These proposals were identified by means of comparison of the geometric distributions of adequate probes around two proposed bioactive conformers of a model of the natural agonist and around two structurally unrelated potent antagonists of PAF, the hetrazepine WEB 2170 and the diarylic compound L-659,989.