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.

中文翻译：

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变构调节：针对大麻素 CB1 受体的替代方法

大麻素CB1受体是G蛋白偶联受体，在许多生物过程和生理功能中发挥重要作用。在过去的 20 年里，已经发现或开发了多种 CB1 受体激动剂和拮抗剂，包括内源性大麻素、植物大麻素和合成大麻素。2005年，人们发现CB1受体含有可以被小分子或变构调节剂识别的变构位点。许多CB1受体变构调节剂，无论是正向还是负向，均已被报道，重要的是，它们表现出与正构激动剂和拮抗剂不同的药理学特征。鉴于通常与 CB1 受体激动剂和拮抗剂/反向激动剂相关的精神作用，变构调节可能提供另一种方法来获得潜在的治疗益处，同时避免正构配体固有的副作用。这篇综述详细介绍了这些变构调节剂的复杂药理学特征、它们的结构-活性关系，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发展可能会改善 CB1 介导的神经系统疾病的治疗方法。