RTICBM-74 Is a Brain-Penetrant Cannabinoid Receptor Subtype 1 Allosteric Modulator that Reduces Alcohol Intake in Rats.

Autor: Lovelock DF; Bowles Center for Alcohol Studies (D.F.L., K.V.V., J.B.) and Department of Psychiatry (J.B.), University of North Carolina - Chapel Hill, Chapel Hill, North Carolina; and Research Triangle Institute, Research Triangle Park, North Carolina (T.N., Y.Z.)., Nguyen T; Bowles Center for Alcohol Studies (D.F.L., K.V.V., J.B.) and Department of Psychiatry (J.B.), University of North Carolina - Chapel Hill, Chapel Hill, North Carolina; and Research Triangle Institute, Research Triangle Park, North Carolina (T.N., Y.Z.)., Van Voorhies K; Bowles Center for Alcohol Studies (D.F.L., K.V.V., J.B.) and Department of Psychiatry (J.B.), University of North Carolina - Chapel Hill, Chapel Hill, North Carolina; and Research Triangle Institute, Research Triangle Park, North Carolina (T.N., Y.Z.)., Zhang Y; Bowles Center for Alcohol Studies (D.F.L., K.V.V., J.B.) and Department of Psychiatry (J.B.), University of North Carolina - Chapel Hill, Chapel Hill, North Carolina; and Research Triangle Institute, Research Triangle Park, North Carolina (T.N., Y.Z.) joyce_besheer@med.unc.edu yzhang@rti.org., Besheer J; Bowles Center for Alcohol Studies (D.F.L., K.V.V., J.B.) and Department of Psychiatry (J.B.), University of North Carolina - Chapel Hill, Chapel Hill, North Carolina; and Research Triangle Institute, Research Triangle Park, North Carolina (T.N., Y.Z.) joyce_besheer@med.unc.edu yzhang@rti.org.
Jazyk: angličtina
Zdroj: The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2022 Mar; Vol. 380 (3), pp. 153-161. Date of Electronic Publication: 2021 Dec 20.
DOI: 10.1124/jpet.121.000919
Abstrakt: The endocannabinoid system is implicated in the neuronal mechanisms of alcohol use disorder (AUD), with the cannabinoid receptor subtype 1 (CB 1 ) representing a promising target for AUD therapeutic interventions. We have previously shown negative allosteric modulators (NAMs) of the CB 1 receptor attenuated the reinstatement of other drugs of abuse including cocaine and methamphetamine in rats; however, their effects on alcohol-related behaviors have not been investigated. Here, we tested the pharmacokinetic properties of one such CB 1 NAM, RTICBM-74, and its effects on alcohol self-administration in rats. RTICBM-74 showed low aqueous solubility and high protein binding but had excellent half-life and low clearance against rat liver microsomes and hepatocytes, and excellent brain penetrance in rats. RTICBM-74 pretreatment specifically reduced alcohol intake across a range of doses in male or female Wistar or Long-Evans rats that were trained to self-administer alcohol. These effects were similar to the CB 1 antagonist/inverse agonist rimonabant, which was tested as a positive control. Importantly, RTICBM-74 was effective at reducing alcohol intake at doses that did not affect locomotion or sucrose self-administration. Our findings suggest that CB 1 NAMs such as RTICBM-74 have promising therapeutic potential in treatment of AUD. SIGNIFICANCE STATEMENT: The present work shows that a metabolically stable and brain-penetrant cannabinoid receptor subtype 1 negative allosteric modulator reduces alcohol self-administration in rats without affecting locomotion or sucrose self-administration, suggesting potential therapeutic relevance for the treatment of alcohol use disorder.
(Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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