RTICBM-74 is a Brain-Penetrant CB 1 Receptor 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 works shows that a newly developed CB1 NAM with an excellent pharmacokinetic profile reduces alcohol self-administration in rats, suggesting potential therapeutic relevance for the treatment of AUD.