Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Molecules. 2021 Sep 6;26(17):5413. doi: 10.3390/molecules26175413.
The CB1 cannabinoid receptor is a G-protein coupled receptor highly expressed throughout the central nervous system that is a promising target for the treatment of various disorders, including anxiety, pain, and neurodegeneration. Despite the wide therapeutic potential of CB1, the development of drug candidates is hindered by adverse effects, rapid tolerance development, and abuse potential. Ligands that produce biased signaling-the preferential activation of a signaling transducer in detriment of another-have been proposed as a strategy to dissociate therapeutic and adverse effects for a variety of G-protein coupled receptors. However, biased signaling at the CB1 receptor is poorly understood due to a lack of strongly biased agonists. Here, we review studies that have investigated the biased signaling profile of classical cannabinoid agonists and allosteric ligands, searching for a potential therapeutic advantage of CB1 biased signaling in different pathological states. Agonist and antagonist bound structures of CB1 and proposed mechanisms of action of biased allosteric modulators are used to discuss a putative molecular mechanism for CB1 receptor activation and biased signaling. Current studies suggest that allosteric binding sites on CB1 can be explored to yield biased ligands that favor or hinder conformational changes important for biased signaling.
CB1 cannabinoid 受体是一种高度表达于中枢神经系统的 G 蛋白偶联受体，是治疗各种疾病（包括焦虑、疼痛和神经退行性疾病）的有希望的靶点。尽管 CB1 具有广泛的治疗潜力，但由于不良反应、快速耐受发展和滥用潜力，药物候选物的开发受到阻碍。产生偏置信号的配体（即优先激活信号转导蛋白而损害另一种信号转导蛋白）已被提议作为一种策略，用于分离各种 G 蛋白偶联受体的治疗和不良反应。然而，由于缺乏强偏置激动剂，CB1 受体的偏置信号传递机制了解甚少。本文综述了研究人员对经典大麻素激动剂和变构配体的偏置信号特征的研究，探讨了 CB1 偏置信号在不同病理状态下的潜在治疗优势。使用 CB1 激动剂和拮抗剂结合结构以及偏置变构调节剂的作用机制，讨论了 CB1 受体激活和偏置信号传递的假设分子机制。目前的研究表明，可以探索 CB1 上的变构结合位点，以产生有利于或阻碍偏置信号传递的重要构象变化的偏置配体。
