Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Department of Chemistry, Division of Sciences, University of Otago, Dunedin, New Zealand.
Trends Pharmacol Sci. 2022 Sep;43(9):754-771. doi: 10.1016/j.tips.2022.06.010. Epub 2022 Jul 26.
Cannabinoid Receptor 2 (CB2) is a G protein-coupled receptor (GPCR) with considerable, though as yet unrealised, therapeutic potential. Promising preclinical data supports the applicability of CB2 activation in autoimmune and inflammatory diseases, pain, neurodegeneration, and osteoporosis. A diverse pharmacopoeia of cannabinoid ligands is available, which has led to considerable advancements in the understanding of CB2 function and extensive preclinical evaluation. However, until recently, most CB2 ligands were highly lipophilic and as such not optimal for clinical application due to unfavourable physicochemical properties. A number of strategies have been applied to develop CB2 ligands to achieve closer to 'drug-like' properties and a few such compounds have now undergone clinical trial. We review the current state of CB2 ligand development and progress in optimising physicochemical properties, understanding advanced molecular pharmacology such as functional selectivity, and clinical evaluation of CB2-targeting compounds.
大麻素受体 2（CB2）是一种 G 蛋白偶联受体（GPCR），具有相当大的、但尚未实现的治疗潜力。有前景的临床前数据支持 CB2 激活在自身免疫和炎症性疾病、疼痛、神经退行性变和骨质疏松症中的适用性。有各种各样的大麻素配体可供选择，这使得人们对 CB2 功能的理解有了很大的进展，并进行了广泛的临床前评估。然而，直到最近，大多数 CB2 配体都是高度亲脂性的，因此由于不理想的物理化学性质，不适合临床应用。已经应用了许多策略来开发 CB2 配体，以实现更接近“药物样”的特性，并且现在已经有一些这样的化合物进行了临床试验。我们回顾了 CB2 配体开发的现状以及在优化物理化学性质、理解功能选择性等先进分子药理学以及 CB2 靶向化合物的临床评估方面的进展。
