A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects
A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects
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DOI：
10.1038/npp.2015.148
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发表时间：
2015-12-01
影响因子：
7.6
通讯作者：
Ross, Ruth A.
中科院分区：
文献类型：
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作者：
Ignatowska-Jankowska, Bogna M.;Baillie, Gemma L.;Ross, Ruth A.
CB1受体是治疗包括疼痛相关疾病状态在内的几种疾病的一个很有前途的靶点。然而，由于精神活性副作用，Delta(9)-四氢大麻酚和其他CB1正构体受体激动剂的治疗应用仍然有限。阳性变构调节剂(PAM)提供了一种替代方法来增强CB1受体的功能，以获得治疗收益，并有望减少副作用。在这里，我们描述了新型合成的CB1 PAM的开发，6-甲基-3-(2-硝基-1-(噻吩基)乙基)-2-苯基-H-1-吲哚(ZCZ011)，它增强了CB1邻位立体激动剂CP55,940和N-花生四烯基乙醇胺(AEA)的体内外药理作用。ZCZ011可增强[H-3]CP55,940与Cb1受体的结合，增强AEA刺激的小鼠脑膜上[(3)5S]GTP-γS的结合，增强HCB(1)细胞中β-arrestin的募集和ERK的磷酸化。在整个动物中，ZCZ011是脑穿透的，在小鼠的行为测试中增加了这些正构体激动剂的效力，指示大麻仿制活性，包括抗伤害性、体温过低、嗜睡、运动活动，以及在药物识别范例中。单独给予ZCZ011在这些实验中没有活性，也没有产生条件性位置偏爱或厌恶，但在神经病理性疼痛的慢性缩窄神经损伤模型和炎症性疼痛的卡拉胶模型中，ZCZ011诱导了CB1受体介导的抗伤害感受效应。这些数据表明，ZCZ011作为CB1 PAM发挥作用，并首次证明CB1 PAM提供了一种有前景的治疗神经性和炎症性疼痛的策略，具有最小或没有类似大麻的副作用。
The CB1 receptor represents a promising target for the treatment of several disorders including pain-related disease states. However, therapeutic applications of Delta(9)-tetrahydrocannabinol and other CB1 orthosteric receptor agonists remain limited because of psychoactive side effects. Positive allosteric modulators (PAMs) offer an alternative approach to enhance CB1 receptor function for therapeutic gain with the promise of reduced side effects. Here we describe the development of the novel synthetic CB1 PAM, 6-methyl-3-(2-nitro-1-(thiophen2- yl)ethyl)-2-phenyl-H-1-indole (ZCZ011), which augments the in vitro and in vivo pharmacological actions of the CB1 orthosteric agonists CP55,940 and N-arachidonoylethanolamine (AEA). ZCZ011 potentiated binding of [H-3]CP55,940 to the CB1 receptor as well as enhancing AEA-stimulated [(3)5S]GTP gamma S binding in mouse brain membranes and beta-arrestin recruitment and ERK phosphorylation in hCB(1) cells. In the whole animal, ZCZ011 is brain penetrant, increased the potency of these orthosteric agonists in mouse behavioral assays indicative of cannabimimetic activity, including antinociception, hypothermia, catalepsy, locomotor activity, and in the drug discrimination paradigm. Administration of ZCZ011 alone was devoid of activity in these assays and did not produce a conditioned place preference or aversion, but elicited CB1 receptor-mediated antinociceptive effects in the chronic constriction nerve injury model of neuropathic pain and carrageenan model of inflammatory pain. These data suggest that ZCZ011 acts as a CB1 PAM and provide the first proof of principle that CB1 PAMs offer a promising strategy to treat neuropathic and inflammatory pain with minimal or no cannabimimetic side effects.