Carruthers Emma R, Grimsey Natasha L
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.
Br J Pharmacol. 2024 Jul;181(14):2247-2269. doi: 10.1111/bph.16172. Epub 2023 Aug 4.
Cannabinoid CB receptor agonists are in development as therapeutic agents, including for immune modulation and pain relief. Despite promising results in rodent preclinical studies, efficacy in human clinical trials has been marginal to date. Fundamental differences in ligand engagement and signalling responses between the human CB receptor and preclinical model species orthologues may contribute to mismatches in functional outcomes. This is a tangible possibility for the CB receptor in that there is a relatively large degree of primary amino acid sequence divergence between human and rodent. Here, we summarise CB receptor gene and protein structure, assess comparative molecular pharmacology between CB receptor orthologues, and review the current status of preclinical to clinical translation for drugs targeted at the CB receptor, focusing on comparisons between human, mouse and rat receptors. We hope that raising wider awareness of, and proposing strategies to address, this additional challenge in drug development will assist in ongoing efforts toward successful therapeutic translation of drugs targeted at the CB receptor. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.
大麻素CB受体激动剂正在作为治疗药物进行研发，包括用于免疫调节和缓解疼痛。尽管在啮齿动物临床前研究中取得了有前景的结果，但迄今为止，在人类临床试验中的疗效甚微。人类CB受体与临床前模型物种直系同源物之间在配体结合和信号反应方面的根本差异，可能导致功能结果不匹配。对于CB受体而言，这是一种切实存在的可能性，因为人类和啮齿动物之间存在相对较大程度的一级氨基酸序列差异。在这里，我们总结CB受体的基因和蛋白质结构，评估CB受体直系同源物之间的比较分子药理学，并回顾针对CB受体的药物从临床前到临床转化的现状，重点是人类、小鼠和大鼠受体之间的比较。我们希望提高对药物研发中这一额外挑战的认识，并提出应对策略，这将有助于正在进行的针对CB受体药物的成功治疗性转化的努力。相关文章：本文是主题为“G蛋白偶联受体的治疗靶向：2021年澳大利亚临床与实验药理学家和毒理学家协会虚拟年度科学会议的热门话题”的一部分。要查看本节中的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc。
