DESIGN AND MODELING OF NEW PLATELET-ACTIVATING-FACTOR ANTAGONISTS .1.SYNTHESIS AND BIOLOGICAL-ACTIVITY OF 4-BIS(3',4',5'-TRIMETHOXYBENZOYL)-2-[[(SUBSTITUTED CARBONYL AND CARBAMOYL)OXY]METHYL]PIPERAZINES

To further investigate our hypothesis on the structure of the platelet -activating factor (PAF) receptor, 35 compounds derived from 1,4-bis(3 ',4',5'-trimethoxybenzoyl)piperazine were synthesized and their in vit ro antagonistic effect was measured. Substitution of the compounds in position 2, by ester or carbamate groups, giving increased steric hind rance and hydrophobicity, increased the platelet aggregation inhibitor y activity from 2 muM (without substitution, compound 2) to 0.07 muM ( compound 1h) arid gave a maximum displacement of [H-3]PAF from platele t membrane of 0.05 muM (compound 1k). It appears that the PAF antagoni stic effect is only weakly enantiospecific, as observed in many cases including antagonists structurally related or not to PAF. 3D electrost atic potential maps (calculated at -10 kcal/mol) of such compounds rev ealed a double ''Cache-oreilles'' (ear-muffs) system. One of these sys tems has been previously described (distance between atoms generating negative wells, 11-14 angstrom). The second shorter ''Cache-oreilles'' (6-7 angstrom) system appears to be required for increased PAF antago nistic activity. This short distance between groups generating the neg ative wells is present in the gingkolides, a series of naturally occur ring PAF antagonists. The present study indicates that the structure o f the PAF receptor may be more complicated than our initial hypothesis and may be a tetrapolarized structure, with alternants of electroposi tive and hydrophobic areas. This modified hypothesis is in agreement w ith recent publications concerning PAF antagonists bearing a cationic moiety.