Human Blood Platelet Aggregation-inhibitory Target Sites Assumed to Involve Membrane Phospholipids

In an extensive study identifying structural features associated with the inhibition of adhesion-release-aggregation chain reactions in human blood platelets, The authors employed a series of carbamoylpiperidine derivatives. The entities conceptualized and synthesized in the laboratories inhibit platelet aggregation (culminating at 5 mu M concentrations) by penetrating the lipid bilayer of the platelet membrane and by interacting, as cations, with negatively charged phospholipids (e.g., phosphatidylserine and phosphatidylinositol) within the bilayer's inner segment. Following such penetration, those cations could be interfering with phospholipase-A sub(2) activation by counteracting stimulus-induced mobilization of Ca super(++) ions and Ca super(++)-dependent phospholipase-A sub(2) activity, thereby rendering platelets less susceptible to aggregation reactions. To confirm these interpretations, the effects of carbamoylpiperidine derivatives are being evaluated at surface pressures estimated to occur in actual platelet membranes (34 mN m super(-1))(9), on monomolecular films of phosphatidylserine whose location in the inner segment of the platelet membrane's lipid bilayer is acknowledged, on those of phosphatidylcholine, which is known to be a constituent of the bilayer's outer leaflet, and on related pure and mixed monolayer systems; e.g., cholesterol/phospholipid in ratios of 0.5, paralleling those observed in platelet membranes (10).