PAF-receptor. 1. 'Cache-oreilles' effect of selected high-potency platelet-activating factor (PAF) antagonists.
Three-dimensional electrostatic maps were calculated for six potent antagonists of platelet-activating factor (PAF), the antagonists being selected for their apparent structural heterogeneity. The molecules examined were the compact Ginkgolides BN 52020, BN 52021 and BN 52022 (1, 2 and 3), the semi-rigid kadsurenone (4), a flexible synthetic dinor type C furanoid lignan L-652,731 (5a) and the triazolothienobenzodiazepine WEB 2086 (7). Calculation of the electrostatic potential generated around all the above molecules showed the existence of two wells of negative potential or 'cache-oreilles' (ear-muffs), i.e., the isocontours drawn at -10 kcal/mol, located at 180 degrees from each other and separated by a maximum distance of 22-27 A. Except for the synthetic dinor type C furanoid lignan (5a), the molecules also presented a moderate hydrophobic fragment, which constitutes a third point of interaction with the high-affinity binding site in rabbit and human platelets. The findings of the present study allow speculation that this high-affinity acceptor site may be a 'polarized cylinder' with a diameter of 10-12 A.
Dive
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Laboratoire de Microbiologie, Institut de Chimie, Liège, Belgium.
Godfroid
J J
JJ
Lamotte-Brasseur
J
J
Batt
J P
JP
Heymans
F
F
Dupont
L
L
Braquet
P
P
D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D004224:Diterpenes; D004563:Electrochemistry; D046934:Ginkgolides; D006801:Humans; D066298:In Vitro Techniques; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D017705:Lignans; D015394:Molecular Structure; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
D001381:Azepines; D001572:Benzofurans; D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D017705:Lignans; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086; C058295:ginkgolide C; C044540:kadsurenone; C045856:ginkgolide B