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

TitleDiscovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake.
Publication TypeJournal Article
Year of Publication2018
AuthorsJin C, Decker AM, Makhijani VH, Besheer J, Darcq E, Kieffer BL, Maitra R
JournalJ Med Chem
Volume61
Issue15
Pagination6748-6758
Date Published2018 Aug 09
ISSN1520-4804
Abstract

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 EC 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 (1 R,2 R)-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.

DOI10.1021/acs.jmedchem.8b00566
Alternate JournalJ. Med. Chem.
PubMed ID30011199
PubMed Central IDPMC6108082
Grant ListR21 MH103708 / MH / NIMH NIH HHS / United States