Allosteric Modulation of the CB1 Receptor

Abstract Alcohol use disorder (AUD) represents a significant burden on human health and society. Existing medications to treat AUD (acamprosate, disulfiram, and naltrexone) have modest efficacy and thus there is continued emphasis on developing novel and effective drugs. The cannabinoid type-1 (CB1) receptor represents a promising AUD treatment target with a clearly demonstrated role in modulating many alcohol-related behaviors and having contributions to the motivational and reinforcing properties of ethanol. The CB1 antagonist/inverse agonist rimonabant effectively reduces alcohol consumption/self-administration, withdrawal severity, and cue- induced relapse. Unfortunately, rimonabant was withdrawn in Europe after its initial approval for obesity treatment because of untoward side effects in humans including anxiety and depression, and development of other CB1 antagonists/inverse agonists has also been halted. As an alternative strategy, our team has synthesized and characterized a library of CB1 receptor negative allosteric modulators (NAMs), ligands that bind to a distinct site than the orthosteric site(s) and modulate the effects of the orthosteric ligands. CB1 NAMs have been shown to effectively block agonist signaling in multiple in vitro assays, similar to rimonabant. Our studies demonstrated that RTICBM-74, a CB1 NAM developed by our team, dose-dependently reduced alcohol consumption without affecting sucrose intake in rats. Importantly, RTICBM-74 showed no anxiety-like behavior at the same dose in an elevated plus maze (EPM) and an open field, whereas rimonabant displayed anxiety-like behavior with decreased time in the open arm in EPM. The goal of this proposal is to further optimize these promising CB1 NAMs to improve the overall properties, particularly increasing solubility and decreasing lipophilicity (Aims 1-2), and evaluate their effects on alcohol self-administration, relapse-like behavior, anxiety- related behavior and anhedonia in rats (Aim 3). Together, these studies have the potential to identify novel CB1 NAMs as a possible therapeutic strategy for the treatment of AUD.