Characterization and distribution of binding sites for [3H]-SR 141716A, a selective brain (CB1) cannabinoid receptor antagonist, in rodent brain

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Life Sciences, 58(15), 1239-1247 (1996) .


SR 141716A belongs to a new class of compounds (diarylpyrazole) that inhibits brain carmabinoid receptors (CB1) and . The present study showed that [3H]-SR 141716A binds with high affinity (Kd = 0.61 ± 0.06 nM) to a homogenous population of binding sites (Bmax = 0.72 ± 0.05 pmol/mg of protein) in rat whole brain (minus cerebellum) synaptosomes. This specific binding was displaced by known cannabinoid receptor ligands with the following rank order of potency SR 141716A > CP 55,940 > WIN 55212-2 = Δ9-THC > anandamide. Apart from anandamide, all these compounds were found to interact competitively with the binding sites labeled by [3H]-SR 141716A. On the other hand, agents lacking affinity for cannabinoid receptors were unable to displace [3H]-SR 141716A from its binding sites (IC50 > 10 μM). In addition, the binding of [3H]-SR 141716A was insensitive to guanyl nucleotides. Regional rat brain distribution of CB1 cannabinoid receptors detected by [3H]-SR 141716A saturation binding and autoradiographic studies, showed that this distribution was very similar to that found for [3H]-CP 55,940. , the [3H]-SR 141716A binding was displaced by SR 141716A with ED50 values of 0.39 ± 0.07 and 1.43 ± 0.29 mg/kg following intraperitoneal and oral administration, respectively. Finally, the [3H]-SR 141716A binding sites remained significantly occupied for at least 12 hr following oral administration of 3 mg/kg SR 141716A. Taken together, these results suggest that SR 141716A in its tritiated form is a useful research tool for labeling brain cannabinoid receptors (CB1) and .

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