Nguyen Thuy, Li Jun-Xu, Thomas Brian F, Wiley Jenny L, Kenakin Terry P, Zhang Yanan
Research Triangle Institute, Research Triangle Park, North Carolina.
Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York.
Med Res Rev. 2017 May;37(3):441-474. doi: 10.1002/med.21418. Epub 2016 Nov 23.
The cannabinoid CB1 receptor is a G protein coupled receptor and plays an important role in many biological processes and physiological functions. A variety of CB1 receptor agonists and antagonists, including endocannabinoids, phytocannabinoids, and synthetic cannabinoids, have been discovered or developed over the past 20 years. In 2005, it was discovered that the CB1 receptor contains allosteric site(s) that can be recognized by small molecules or allosteric modulators. A number of CB1 receptor allosteric modulators, both positive and negative, have since been reported and importantly, they display pharmacological characteristics that are distinct from those of orthosteric agonists and antagonists. Given the psychoactive effects commonly associated with CB1 receptor agonists and antagonists/inverse agonists, allosteric modulation may offer an alternate approach to attain potential therapeutic benefits while avoiding inherent side effects of orthosteric ligands. This review details the complex pharmacological profiles of these allosteric modulators, their structure-activity relationships, and efforts in elucidating binding modes and mechanisms of actions of reported CB1 allosteric modulators. The ultimate development of CB1 receptor allosteric ligands could potentially lead to improved therapies for CB1-mediated neurological disorders.
大麻素CB1受体是一种G蛋白偶联受体，在许多生物学过程和生理功能中发挥着重要作用。在过去20年里，人们发现或开发了多种CB1受体激动剂和拮抗剂，包括内源性大麻素、植物性大麻素和合成大麻素。2005年，人们发现CB1受体含有可被小分子或变构调节剂识别的变构位点。此后，已报道了许多CB1受体变构调节剂，包括正向和负向调节剂，重要的是，它们表现出与正位激动剂和拮抗剂不同的药理学特性。鉴于CB1受体激动剂和拮抗剂/反向激动剂通常具有精神活性作用，变构调节可能提供一种替代方法，以获得潜在的治疗益处，同时避免正位配体的固有副作用。本综述详细介绍了这些变构调节剂的复杂药理学特征、它们的构效关系，以及在阐明已报道的CB1变构调节剂的结合模式和作用机制方面所做的努力。CB1受体变构配体的最终开发可能会为CB1介导的神经系统疾病带来更好的治疗方法。
