trans-2,5-Bis-(3,4,5-trimethoxyphenyl)tetrahydrofuran. An orally active specific and competitive receptor antagonist of platelet activating factor.
trans-2,5-Bis(3,4,5-trimethoxyphenyl)tetrahydrofuran (L-652,731) is found to be a potent and orally active platelet activating factor (PAF)-specific and competitive receptor antagonist. It potently inhibits [3H]PAF (1 nM) binding to receptor sites on rabbit platelet membranes with an ED50 of 2 X 10(-8) M under the assay condition without the addition of mono- or divalent cations. In a comparative study, it is more potent than CV-3988, kadsurenone, and ginkgolide B as a receptor antagonist. The equilibrium dissociation constants (KB) of L-652,731 obtained either from the inhibition of receptor binding or from the inhibition of PAF-induced aggregation of gel-filtered rabbit platelet are 2.7 X 10(-8) and 2.1 X 10(-8) M, respectively. The agreement of these KB determinations based on receptor and cellular function suggests that L-652,731 does not inhibit other steps following PAF-receptor binding. L-652,731 does not antagonize the binding of several radioligands to their respective receptor. It shows no inhibitory effect on platelet aggregation induced by other aggregating agents including thrombin, collagen, A-23187, arachidonic acid, epinephrine, and ADP. L-652,731 is orally active; it inhibits PAF-induced rat cutaneous vascular permeability with an ED50 of 30 mg/kg orally. Significant inhibitory results of L-652,731 suggest that PAF may be partially involved in cutaneous vascular permeability induced by histamine and bradykinin.
D000818:Animals; D001572:Benzofurans; D001578:Benzopyrans / Q000494:pharmacology; D001792:Blood Platelets / Q000032:analysis; D001920:Bradykinin / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000494:pharmacology*; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D017705:Lignans; D008274:Magnesium / Q000378:metabolism; D008433:Mathematics; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D012964:Sodium / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology
D001572:Benzofurans; D001578:Benzopyrans; D005663:Furans; D017705:Lignans; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles; C039351:platelet activating factor receptor; D006632:Histamine; C037913:CV 3988; C044540:kadsurenone; C047504:2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran; D012964:Sodium; D008274:Magnesium; D001920:Bradykinin