Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
J Med Chem. 2019 Aug 22;62(16):7557-7574. doi: 10.1021/acs.jmedchem.9b00869. Epub 2019 Aug 1.
G protein-coupled receptor 68 (GPR68) is an understudied orphan G protein-coupled receptor (GPCR). It is expressed most abundantly in the brain, potentially playing important roles in learning and memory. Pharmacological studies with GPR68 have been hindered by lack of chemical tools that can selectively modulate its activity. We previously reported the first small-molecule positive allosteric modulator (PAM), ogerin (), and showed that can potentiate proton activity at the GPR68-G pathway. Here, we report the first comprehensive structure-activity relationship (SAR) study on the scaffold of . Our lead compound resulted from this study, MS48107 (), displayed 33-fold increased allosteric activity compared to . Compound demonstrated high selectivity over closely related proton GPCRs and 48 common drug targets, and was bioavailable and brain-penetrant in mice. Thus, our SAR study has resulted in an improved GPR68 PAM for investigating the physiological and pathophysiological roles of GPR68 in vitro and in vivo.
G 蛋白偶联受体 68（GPR68）是一种研究较少的孤儿 G 蛋白偶联受体（GPCR）。它在大脑中表达最为丰富，可能在学习和记忆中发挥重要作用。由于缺乏能够选择性调节其活性的化学工具，对 GPR68 的药理学研究受到了阻碍。我们之前报道了第一个小分子正变构调节剂（PAM）ogerin（），并表明 可以增强 GPR68-G 途径的质子活性。在这里，我们报告了第一个关于 的全面结构-活性关系（SAR）研究。我们的先导化合物 MS48107（）源自这项研究，与 相比，其变构活性增加了 33 倍。化合物 表现出与密切相关的质子 GPCR 和 48 个常见药物靶标高度的选择性，并且在小鼠中具有生物利用度和脑穿透性。因此，我们的 SAR 研究产生了一种改进的 GPR68 PAM，可用于在体外和体内研究 GPR68 的生理和病理生理作用。
