Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake

The orphan G-protein-coupled receptor
GPR88 is highly expressed
in the striatum. Studies using GPR88 knockout mice have suggested
that the receptor is implicated in alcohol seeking and drinking behaviors.
To date, the biological effects of GPR88 activation are still unknown
due to the lack of a potent and selective agonist appropriate for
in vivo investigation. In this study, we report the discovery of the
first potent, selective, and brain-penetrant GPR88 agonist RTI-13951-33
(6). RTI-13951-33 exhibited an EC50 of 25
nM in an in vitro cAMP functional assay and had no significant off-target
activity at 38 GPCRs, ion channels, and neurotransmitter transporters
that were tested. RTI-13951-33 displayed enhanced aqueous solubility
compared to (1R,2R)-2-PCCA (2) and had favorable pharmacokinetic properties for behavioral
assessment. Finally, RTI-13951-33 significantly reduced alcohol self-administration
and alcohol intake in a dose-dependent manner without effects on locomotion
and sucrose self-administration in rats when administered intraperitoneally.