CIS-19, a novel platelet activating factor receptor antagonist: In vitro and in vivo studies

Abstract

The effects of CIS-19 ( cis-2-(3,4-dimethoxyphenyl)-6-isopropoxy-7-methoxyl-1-( N-methylformamido)-1,2,3,4-tetrahydronaphthalene) was determined in vitro in rabbit platelets and in vivo in rats and guinea-pigs. CIS-19 inhibited in a selective and concentration-dependent manner the aggregation and ATP release reaction of rabbit platelets induced by PAF (4 nM). The IC 50 values of CIS-19 on PAF-induced aggregation of washed platelets and platelet-rich plasma were 11.3 ± 2.7 and 16.8 ± 3.0 μM respectively. BN52021 also inhibited PAF-induced aggregation of washed platelets with an IC 50 value of 11.7 ± 2.8 μM. CIS-19 inhibited [ 3H]PAF (4 nM) binding to washed rabbit platelets with an IC 50 value 1.5 ± 0.2 μM. The concentration-response curve of PAF-induced aggregation of washed platelets was shifted rightwards by CIS-19 with p A 2 and p A 10 values of 7.1 (6.8–7.3 for 95% confidence limit) and 6.1 (5.8–6.2) respectively. The thromboxane B 2 formation of washed platelets caused by AA, collagen or thrombin was not affected by CIS-19 of concentrations below 400 μM. CIS-19 (25 μM) completely blocked PAF-induced, but not collagen- or thrombin-induced [ 3H]inositol monophosphate formation of washed platelets. When CIS-19 (2.5 and 5 mg/kg) was injected i.v. into the femoral vein, it did not affect the blood pressure of rats, but antagonized PAF (2.5 μg/kg, i.v.)-induced hypotensive shock either preventively or curatively. CIS-19 (2.5 and 5 mg/kg) also blocked PAF (50 ng/kg)-induced, but not AA (50 μg/kg)-induced, bronchoconstriction in guinea-pigs. It is concluded that CIS-19 is an effective PAF receptor antagonist not only in vitro, but also in vivo.