Conformational analysis of a diene analog of isocarbacyclin and prostacyclin.

Abstract

A diene analog (2) of isocarbacyclin has been found to be a potent inhibitor of platelet aggregation. A molecular mechanics calculation study on model compounds of both prostacyclin (1) and 2 was undertaken in an attempt to elucidate the stereochemical properties and to find the active conformers. At first the ring structures were investigated, then the directions of the a-chain and finally the entire model compounds were studied. A working hypothesis that four functional groups, consisting of a carboxyl group of the a-chain, a hydroxyl group at position 11, another hydroxyl group of the ω-chain and a π-electron system at the 5, 6 and 6a positions, play an important role in binding with a receptor to elicit activities is presented. Three-dimensional arrangements of these essential functional groups in stable conformations were examined by superimposing the coordinates of the four groups of 2 on those of 1, because these moieties in the receptor-bound conformations should be identically located in both molecules. Three candidates for the active conformers are presented as a basis for a rational approach to the design of prostacyclin agonists.