Design, Synthesis, and Characterization of Ogerin-Based Positive Allosteric Modulators for G Protein-Coupled Receptor 68 (GPR68)

Xufen Yu, Xi Ping Huang, Terry P. Kenakin, Samuel T. Slocum, Xin Chen, Michael L. Martini, Jing Liu, Jian Jin

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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 (1), and showed that 1 can potentiate proton activity at the GPR68-Gs pathway. Here, we report the first comprehensive structure-activity relationship (SAR) study on the scaffold of 1. Our lead compound resulted from this study, MS48107 (71), displayed 33-fold increased allosteric activity compared to 1. Compound 71 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.

Original languageEnglish
Pages (from-to)7557-7574
Number of pages18
JournalJournal of Medicinal Chemistry
Volume62
Issue number16
DOIs
StatePublished - 22 Aug 2019

Fingerprint

Dive into the research topics of 'Design, Synthesis, and Characterization of Ogerin-Based Positive Allosteric Modulators for G Protein-Coupled Receptor 68 (GPR68)'. Together they form a unique fingerprint.

Cite this