CV-6209, a highly potent antagonist of platelet activating factor in vitro and in vivo.

2-[N-acetyl-N-(2-methoxy-3-octadecylcarbamoyloxypropoxycarbonyl) aminomethyl]-1-ethylpyridinium chloride (CV-6209) inhibited aggregation of rabbit and human platelets induced by platelet activating factor (PAF) with the IC50 values of 7.5 X 10(-8) and 1.7 X 10(-7) M, respectively, and had little effects on the aggregation induced by arachidonic acid, ADP and collagen. The inhibitory effect of CV-6209 on the PAF-induced rabbit platelet aggregation was 104, 9, 8 and 3 times more potent than the PAF antagonists CV-3988, ONO-6240, Ginkgolide B and etizolam, respectively. CV-6209 inhibited [3H]serotonin release from rabbit platelets stimulated with PAF (3 X 10(-8) M) with a similar potency as the inhibition on the platelet aggregation. CV-6209 inhibited PAF (0.3 microgram/kg i.v.)-induced hypotension in rats (ED50, 0.009 mg/kg i.v.) with no effect on the hypotension induced by arachidonic acid, histamine, bradykinin and isoproterenol. CV-6209 (1 mg/kg) inhibited slightly the acetylcholine-induced hypotension. In rats, post-treatment with CV-6209 reversed the PAF (1 microgram/kg i.v.)-induced hypotension rapidly (ED50, 0.0046 mg/kg i.v.); CV-6209 was 74, 20, 185 and over 2100 times more potent than CV-3988, ONO-6240, Ginkgolide B and etizolam, respectively. Thus, the relative potency of the anti-PAF action of PAF analog (CV-6209, CV-3988 and ONO-6240) differed little between the inhibition of PAF-induced platelet aggregation and the reversal of PAF-induced hypotension, but that of nonPAF analogs (Ginkgolide B and etizolam) differed greatly with these assay systems, when standardized with CV-6209.(ABSTRACT TRUNCATED AT 250 WORDS)