PAF receptor and "Cache-oreilles" effect. Simple PAF antagonists

Nine simple and structurally flexible PAF antagonists were synthesized and their inhibitory effects on PAF induced platelet aggregation were measured. Compounds with PAF antagonistic activity exhibited a negative electrostatic potential generated by two trimethoxyphenyl groups (isocontour at -10 Kcal/mole) at various distances between the negative clouds. The optimal distance between the atoms generating the "cache-oreilles" system for exhibiting potent PAF antagonistic activity is estimated to be 11-13 A. In the flexible molecules studied, the dispersion of the electronic distribution is not necessarily favorable for anti-PAF activity. The data support the simple bipolarized model for the PAF receptor that has been proposed by the authors.