Characterization and distribution of binding sites for [3H]-SR 141716A, a selective brain (CB1) cannabinoid receptor antagonist, in rodent brain.
Characterization and distribution of binding sites for [3H]-SR 141716A, a selective brain (CB1) cannabinoid receptor antagonist, in rodent brain.
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DOI：
10.1016/0024-3205(96)00085-9
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发表时间：
1996-03
期刊：
影响因子：
6.1
通讯作者：
M. Rinaldi-Carmona;Françoise Pialot;Christian Congy;Elsa Redon;Francis Barth;A. Bachy;J. Breliere;Philippe Soubrié;G. Fur
中科院分区：
文献类型：
--
作者：
M. Rinaldi-Carmona;Françoise Pialot;Christian Congy;Elsa Redon;Francis Barth;A. Bachy;J. Breliere;Philippe Soubrié;G. Fur
SR 141716A是一类体外和体内抑制脑红素受体（CB1）的新化合物（二芳基吡唑）。结果表明，[3H]-SR 141716A在大鼠全脑（不含小脑）突触体中具有高亲和力（Kd= 0.61±0.06 nM）的结合位点（Bmax= 0.72±0.05 pmol/mg蛋白）。这种特异性结合被已知的大麻素受体配体取代，其效价为SR 141716A > CP 55,940 > WIN 55212-2 = Δ9-THC > anandamide。除anandamide外，这些化合物均与[3H]-SR 141716A标记的结合位点发生竞争性相互作用。另一方面，对大麻素受体缺乏亲和力的药物无法将[3H]-SR 141716A从其结合位点上置换（IC50 bb0 10 μM）。此外，[3H]-SR 141716A的结合对鸟苷核苷酸不敏感。[3H]-SR 141716A饱和结合和放射自显影研究发现，大鼠脑CB1大麻素受体的区域分布与[3H]-CP 55,940的分布非常相似。在体内，[3H]-SR 141716A结合被SR 141716A取代，经腹腔和口服后ed50值分别为0.39±0.07和1.43±0.29 mg/kg。最后，在口服3mg /kg SR 141716A后，[3H]-SR 141716A结合位点在至少12小时内仍被显著占据。综上所述，这些结果表明，氚化形式的SR 141716A是体外和体内标记脑大麻素受体（CB1）的有用研究工具。
SR 141716A belongs to a new class of compounds (diarylpyrazole) that inhibits brain carmabinoid receptors (CB1) in vitro and in vivo . 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. In vivo , the [3H]-SR 141716A binding was displaced by SR 141716A with ED50values 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) in vitro and in vivo .