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

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.