Biochemical and pharmacological characterization of L-659,989: an extremely potent, selective and competitive receptor antagonist of platelet-activating factor
L-659,989 [trans-2-(3-methoxy-5-methylsulfonyl-4-propoxy-phenyl)-5-(3,4,5- trimethoxyphenyl)tetrahydrofuran] is a p.o. active and extremely potent, selective and competitive platelet-activating factor (PAF) receptor antagonist. It inhibited [3H]PAF binding to either rabbit platelet or rabbit polymor...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 246; no. 2; pp. 534 - 541 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.08.1988
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Subjects | |
Online Access | Get full text |
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Summary: | L-659,989 [trans-2-(3-methoxy-5-methylsulfonyl-4-propoxy-phenyl)-5-(3,4,5- trimethoxyphenyl)tetrahydrofuran] is a p.o. active
and extremely potent, selective and competitive platelet-activating factor (PAF) receptor antagonist. It inhibited [3H]PAF
binding to either rabbit platelet or rabbit polymorphonuclear leukocyte membranes with an equilibrium inhibition constant
(Kl) of 1.1 nM; whereas in human platelet, human polymorphonuclear leukocyte or human lung membranes, L-659,989 was about
10 times less potent with a Kl of 14.3 nM. The structural specificity of L-659,989 was demonstrated by the low activity of
its cisisomer which was about 100 to 200 times less potent, also the (-)-L-659,989 was found to be 20- to 30-fold more potent
than (+)-L-659,989. In both [3H]PAF binding and PAF-induced platelet aggregation inhibition, L-659,989 was found to be a competitive
inhibitor with an equilibrium dissociation constant (KB) of 1.5 and 1.7 nM, respectively, in rabbit platelets. Even up to
6 microM concentration, L-659,989 showed no inhibition on the aggregation of rabbit platelets in plasma induced by ADP, arachidonic
acid, collagen or thrombin. In an in vivo model, it inhibited guinea pig bronchoconstriction induced by i.v. infusion of 75
ng/kg of PAF with ED50 values of 13 micrograms/kg i.v. and 0.5 mg/kg p.o. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0022-3565 1521-0103 |