Synthesis, biological, and structural explorations of a series of μ-opioid receptor (MOR) agonists with high G protein signaling bias

化学 功能选择性 药理学 内在活性 兴奋剂 受体 类阿片 信号转导 μ-阿片受体 止痛药 立体化学 不利影响 G蛋白偶联受体 生物化学 医学
作者
Yifei Yang,Yonghai Wang,Aixia Zuo,Chunmei Li,Wenyan Wang,Wanglin Jiang,Yanpei Chen,Xin Che,Yang Zhang,Wentao Wu,Xiaobo Cen,Hongbo Wang,Jingwei Tian
出处
期刊:European journal of medicinal chemistry [Elsevier BV]
卷期号:228: 113986-113986 被引量:23
标识
DOI:10.1016/j.ejmech.2021.113986
摘要

Biased agonism refers to the ability of compounds to drive preferred signaling pathways and avoid adverse signaling pathways in a ligand-dependent manner for some G-protein-coupled receptors. It is thought that the separation of therapeutic efficacy (e.g., analgesia) from adverse effects (e.g., respiration depression) can be achieved through the design of biased MOR agonists and one example is the recently approved MOR biased agonist oliceridine (TRV130). However, oliceridine only demonstrates modest beneficial effects as compared to other opioids in terms of therapeutic/adverse effect balance. One possibility attributable to the modest success of oliceridine is its limited bias, and as such developing MOR ligands with a more biased agonism profile could in theory further improve the beneficial effects of the ligands. Here, we rationally designed and synthesized a series of derivatives as potent highly biased MOR agonists (19a-v) through the modification and structure-activity relationship study of TRV130. This novel synthetic molecule, LPM3480392 (19m), demonstrated improved in vitro biased agonism (EC50 = 0.35 nM, Emax = 91.4%) with no measured β-arrestin recruitment (EC50 > 30000 nM, Emax = 1.6%), good brain penetration (B/P ratio = 4.61, 0.25 h post-IV dosing 2.0 mg/kg), a favorable pharmacokinetic profile (distribution volume = 10766 mL/kg, t1/2 = 1.9 h) and produced potent antinociceptive effect with reduced respiratory suppression (sO2(%) = 92.17, 0.32 mg/kg, SC) as compared to TRV130. LPM3480392 has completed preclinical studies and is currently under clinical development (CTR20210370) as an analgesic for the treatment of moderate to severe pain.
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