Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake.
Fiche publication
Date publication
août 2018
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DARCQ Emmanuel
Tous les auteurs :
Jin C, Decker AM, Makhijani VH, Besheer J, Darcq E, Kieffer BL, Maitra R
Lien Pubmed
Résumé
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.
Mots clés
Alcohol Drinking, drug therapy, Animals, Brain, metabolism, Drug Discovery, Female, Male, Rats, Receptors, G-Protein-Coupled, metabolism, Small Molecule Libraries, metabolism
Référence
J Med Chem. 2018 08 9;61(15):6748-6758