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

The endocannabinoid system is implicated in the neuronal mechanisms of alcohol use disorder (AUD), with the cannabinoid receptor subtype 1 (CB1) representing a promising target for AUD therapeutic interventions. We have previously shown negative allosteric modulators (NAMs) of the CB1 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 CB1 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 CB1 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 CB1 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.