CIS-19, a novel platelet activating factor receptor antagonist: in vitro and in vivo studies.
The effects of CIS-19 (cis-2-(3,4-dimethoxyphenyl)-6-isopropoxy-7-methoxyl-1-(N-methylforma mido)-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 IC50 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 microM respectively. BN52021 also inhibited PAF-induced aggregation of washed platelets with an IC50 value of 11.7 +/- 2.8 microM. CIS-19 inhibited [3H]PAF (4 nM) binding to washed rabbit platelets with an IC50 value of 1.5 +/- 0.2 microM. The concentration-response curve of PAF-induced aggregation of washed platelets was shifted rightwards by CIS-19 with pA2 and pA10 values of 7.1 (6.8-7.3 for 95% confidence limit) and 6.1 (5.8-6.2) respectively. The thromboxane B2 formation of washed platelets caused by AA, collagen or thrombin was not affected by CIS-19 of concentrations below 400 microM. CIS-19 (25 microM) 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 micrograms/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 micrograms/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.
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei.
F N
FN
Ko
S M
SM
Yu
I S
IS
Chen
H
H
Ishii
Y L
YL
Chang
T F
TF
Huang
C M
CM
Teng
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D046934:Ginkgolides; D006168:Guinea Pigs; D007022:Hypotension / Q000517:prevention & control; D007295:Inositol Phosphates / Q000096:biosynthesis; D007783:Lactones / Q000494:pharmacology; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000096:biosynthesis
D004224:Diterpenes; D046934:Ginkgolides; D007295:Inositol Phosphates; D007783:Lactones; D010972:Platelet Activating Factor; D011956:Receptors, Cell Surface; D013764:Tetrahydronaphthalenes; D013929:Thromboxane B2; C079137:CIS 19; D000255:Adenosine Triphosphate; C045856:ginkgolide B