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In vitro and in vivo pharmacological profiles of the PAF receptor antagonist SRI 63-675.

We have examined a recently developed PAF antagonist SRI 63-675 (dimethyl-tetrahydrofuran-methoxyphosphinyloxy-ethylquinolinium ) for its ability to inhibit several major PAF-induced physiological responses. The compound was a potent inhibitor of PAF-induced platelet aggregation in platelet rich plasma obtained from humans, guinea pigs, and rabbits, with IC50 values of 3.43, 0.25, and 0.97 microM, respectively. SRI 63-675 did not inhibit ADP, collagen nor epinephrine-induced human platelet aggregation. The IC50 for inhibition of PAF receptor binding to human platelets was 0.37 microM. In the rat SRI 63-675 inhibited 0.1 microgram kg-1 i.v. PAF-induced hypotension, with an ED50 of 32 micrograms kg-1 i.v. Using the same PAF challenge in the guinea pig, SRI 63-675 inhibited the hemoconcentration (ED50 = 17 micrograms kg-1 i.v.) and bronchoconstriction (ED50 = 24 micrograms kg-1 i.v.) responses. In the primate, the ED50 was 28 micrograms kg-1 i.v. against 3.5 micrograms kg-1 PAF-induced hemoconcentration. The ratio (1:6) in the primate of PAF used (6.3 nmol kg-1) to antagonist at the ED50 (40.7 nmol kg-1) indicates exceptional potency of SRI 63-675 in this species. The inhibition by SRI 63-675 of the major PAF-induced effects in the rat, guinea pig and primate suggests a common receptor may be involved in the expression of these PAF responses.