Seven compounds having varying affinities for peripheral benzodiazepine (p sites) were evaluated in vitro as inhibitors of arachidonic acid-induced rabbit platelet aggregation and thromboxane B2 (TXB2) synthesis. With the exception of flumazenil, all compounds inhibited both parameters with IC50 values ranging from 0.19 to 3.5 microM, with a significant correlation between the inhibition of aggregation and the synthesis of thromboxane B2. The antiaggregatory effect was stereoselective, and inhibition was increased when cellular penetration was favoured by increasing the volume of the organic solvent. The order of potency these compounds is consistent with an effect at intracellular p sites (Ro5-4864 > PK14067 > PK 11195 >> PK 14068 > or = clonazepam > or = diazepam >>> flumazenil). However, the correlation between the aggregation inhibition and the synthesis of TXB2 suggests that microsomal cyclooxygenase may be the intracellular target of these ligands. We therefore propose that this enzyme possesses a site for benzodiazepine ligands which may share certain characteristics with the peripheral benzodiazepine receptor.
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