Cannabinoid Discrimination and Antagonism by CB1 Neutral and Inverse Agonist Antagonists
Cannabinoid Discrimination and Antagonism by CB1 Neutral and Inverse Agonist Antagonists
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DOI：
10.1124/jpet.112.201962
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发表时间：
2013-03-01
影响因子：
3.5
通讯作者：
Bergman, Jack
中科院分区：
文献类型：
--
作者：
Kangas, Brian D.;Delatte, Marcus S.;Bergman, Jack
大麻素受体1（CB 1）反向激动剂（例如，利莫那班）已被报道产生包括恶心、呕吐和快感缺乏的副作用，这限制了它们的临床应用。最近的实验室研究表明，CB 1中性拮抗剂的作用不同于这些反向激动剂，提高了改善临床实用性的可能性。然而，关于中性拮抗剂的拮抗剂性质知之甚少。在本研究中，比较了CB 1反向激动剂SR 141716 A（利莫那班）和CB 1中性拮抗剂AM4113在训练辨别新型CB 1完全激动剂AM4054的非人灵长类动物中改变CB 1受体介导的辨别刺激效应的能力。结果表明，AM4054作为一种有效的CB 1辨别刺激，其起效时间和作用过程与CB 1激动剂Delta（9）-四氢大麻酚相当，并且反向激动剂利莫那班和中性拮抗剂AM4113在AM4054剂量-效应曲线中产生剂量相关性的位移，这表明两种药物都可克服地拮抗AM 4054的辨别性刺激作用。Schild分析进一步表明，利莫那班和AM4113产生高度相似的拮抗作用，这在相当的PA（2）值（6.9）中显而易见。结合既往研究，当前数据表明，CB 1中性拮抗剂相对于反向激动剂的安全性特征改善并未伴随CB 1受体拮抗剂作用的丧失。
Cannabinoid receptor 1 (CB1) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB1 neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB1 inverse agonist SR141716A (rimonabant) and the CB1 neutral antagonist AM4113 were compared for their ability to modify CB1 receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB1 full agonist AM4054. Results indicate that AM4054 serves as an effective CB1 discriminative stimulus, with an onset and time course of action comparable with that of the CB1 agonist Delta(9)-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB1 neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB1 receptors.