a College of Pharmacy and Nutrition , University of Saskatchewan , Saskatoon , Canada.
Drug Metab Rev. 2018 Feb;50(1):14-25. doi: 10.1080/03602532.2018.1428341. Epub 2018 Jan 21.
Allosteric modulation of the type 1 cannabinoid receptor (CB1R) holds great therapeutic potential. This is because allosteric modulators do not possess intrinsic efficacy, but instead augment (positive allosteric modulation) or diminish (negative allosteric modulation) the receptor's response to endogenous ligand. Consequently, CB1R allosteric modulators have an effect ceiling which allows for the tempering of CB1R signaling without the desensitization, tolerance, dependence, and psychoactivity associated with orthosteric compounds. Pain, movement disorders, epilepsy, obesity are all potential therapeutic targets for CB1R allosteric modulation. Several challenges exist for the development of CB1R allosteric modulators, such as receptor subtype specificity, translation to in vivo systems, and mixed allosteric/agonist/inverse agonist activity. Despite these challenges, elucidation of crystal structures of CB1R and compound design based on structure-activity relationships will advance the field. In this review, we will cover recent progress for CB1R allosteric modulators and discuss the future promise of this research.
1 型大麻素受体 (CB1R) 的变构调节具有巨大的治疗潜力。这是因为变构调节剂本身没有内在效力，而是增强（正变构调节）或减弱（负变构调节）受体对内源性配体的反应。因此，CB1R 变构调节剂具有作用上限，允许调节 CB1R 信号而不会产生与正构化合物相关的脱敏、耐受、依赖和精神活性。疼痛、运动障碍、癫痫、肥胖都是 CB1R 变构调节的潜在治疗靶点。开发 CB1R 变构调节剂存在一些挑战，例如受体亚型特异性、向体内系统的转化以及混合变构/激动剂/反向激动剂活性。尽管存在这些挑战，但 CB1R 晶体结构的阐明以及基于构效关系的化合物设计将推动该领域的发展。在这篇综述中，我们将介绍 CB1R 变构调节剂的最新进展，并讨论该研究的未来前景。
