Pasternak Gavril W, Childers Steven R, Pan Ying-Xian
Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Physiology/Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Handb Exp Pharmacol. 2020;258:89-125. doi: 10.1007/164_2019_270.
Opioid analgesics, most of which act through mu opioid receptors, have long represented valuable therapeutic agents to treat severe pain. Concerted drug development efforts for over a 100 years have resulted in a large variety of opioid analgesics used in the clinic, but all of them continue to exhibit the side effects, especially respiratory depression, that have long plagued the use of morphine. The recent explosion in fatalities resulting from overdose of prescription and synthetic opioids has dramatically increased the need for safer analgesics, but recent developments in mu receptor research have provided new strategies to develop such drugs. This chapter reviews recent advances in developing novel opioid analgesics from an understanding of mu receptor structure and function. This includes a summary of the mechanism of agonist binding deduced from the crystal structure of mu receptors. It will also highlight the development of novel agonist mechanisms, including biased agonists, bivalent ligands, and allosteric modulators of mu receptor function, and describe how receptor phosphorylation modulates these pathways. Finally, it will summarize research on the alternative pre-mRNA splicing mechanisms that produces a multiplicity of mu receptor isoforms. Many of these isoforms exhibit different pharmacological specificities and brain circuitry localization, thus providing an opportunity to develop novel drugs with increased therapeutic windows.
阿片类镇痛药大多通过μ阿片受体发挥作用，长期以来一直是治疗重度疼痛的重要治疗药物。经过100多年的协同药物研发努力，临床上已使用了多种阿片类镇痛药，但它们都仍存在副作用，尤其是呼吸抑制，这长期以来一直困扰着吗啡的使用。近期因处方阿片类药物和合成阿片类药物过量导致的死亡人数激增，极大地增加了对更安全镇痛药的需求，但μ受体研究的最新进展为开发此类药物提供了新策略。本章从对μ受体结构和功能的理解出发，综述了新型阿片类镇痛药开发的最新进展。这包括从μ受体晶体结构推导的激动剂结合机制的总结。还将重点介绍新型激动剂机制的开发，包括偏向激动剂、双价配体和μ受体功能的变构调节剂，并描述受体磷酸化如何调节这些途径。最后，将总结关于产生多种μ受体亚型的替代性前体mRNA剪接机制的研究。许多这些亚型表现出不同的药理学特异性和脑回路定位，从而为开发具有更宽治疗窗的新型药物提供了机会。
