Allosteric Modulation of the CB1 Receptor

 描述（由申请人提供）：本申请是对PAS-15-029“促进基础神经科学研究”的回应，旨在促进解决基础神经科学基本问题的研究。由于CB 1受体在治疗一系列疾病如肥胖、药物成瘾、疼痛和炎症中的前景，CB 1受体的调节一直是人们非常感兴趣的研究课题。与使用CB 1受体拮抗剂/反向激动剂利莫那班（SR 141716）相关的不良副作用，包括焦虑和抑郁，对大麻素受体拮抗剂的开发及其临床应用产生了不利影响。最近，已经发现了几类小分子CB 1变构调节剂，其提供了非常需要的替代策略来调节CB 1信号传导以获得治疗益处。然而，这些分子的变构调节的具体性质仍不清楚，体外和体内药理学之间似乎缺乏相关性。虽然Org 27569和PSNCBAM-1在许多体外功能测定中充当拮抗剂，但Org 27569在小鼠或大鼠的几种动物模型中不增强或阻断CB 1激动剂诱导的作用。有趣的是，我们发现Org 27569剂量依赖性地减弱了线索和药物诱导的可卡因和甲基苯丙胺寻求行为的恢复。这些发现表明CB 1变构调节剂信号传导是高度通路和探针依赖性的。为了更好地理解CB 1变构调节剂的信号传导机制并开发可能具有通路选择性的改进的分子探针，我们在此提出设计和合成CB 1变构调节剂，并使用一系列体外测定来表征探针对信号传导的依赖性作用，并使用这些探针研究体内模型中的不同信号传导途径，以将疗效的可量化模式与体内表型应答

 DESCRIPTION (provided by applicant): This application is in response to PAS-15-029 "Promoting Research in Basic Neuroscience" which aims to stimulate research addressing fundamental questions in basic neuroscience. Modulation of the CB1 receptor has been a research topic of great interest due to the promise of the CB1 receptor in the treatment of a range of disorders such as obesity, drug addiction, pain and inflammation. The untoward side effects associated with the use of the CB1 receptor antagonist/inverse agonist rimonabant (SR141716), including anxiety and depression, have adversely impacted the development of cannabinoid receptor antagonists and their clinical application. Recently, several classes of small molecule CB1 allosteric modulators have been discovered which offer a much needed alternative strategy to modulate CB1 signaling for therapeutic benefit. However, the specific nature of the allosteric modulation of these molecules remains unclear and there seems to be a lack of correlation between the in vitro and in vivo pharmacology. While Org27569 and PSNCBAM-1 acted as antagonists in a number of in vitro functional assays, Org27569 did not enhance or block CB1 agonist-induced effects in several animal models in mice or rats. Interestingly, we found that Org27569 dose-dependently attenuated both cue- and drug-induced reinstatement of cocaine- and methamphetamine-seeking behavior. These findings suggest CB1 allosteric modulator signaling is highly pathway and probe dependent. To better understand the signaling mechanism of CB1 allosteric modulators and develop improved molecular probes that may be pathway selective, we herein propose to design and synthesize CB1 allosteric modulators, and use an array of in vitro assays to characterize probe dependent effects on signaling, and employ these probes to investigate different signaling pathways in in vivo models to link quantifiable patterns of efficacy with in vivo phenotypic responses.