# Allosteric Modulation of the CB1 Receptor

> **NIH NIH R01** · RESEARCH TRIANGLE INSTITUTE · 2024 · $634,141

## Abstract

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 Unfortunately, rimonabant was withdrawn in Europe after its initial approval for obesity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.

## Key facts

- **NIH application ID:** 10812234
- **Project number:** 5R01AA030509-07
- **Recipient organization:** RESEARCH TRIANGLE INSTITUTE
- **Principal Investigator:** Joyce Besheer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $634,141
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812234

## Citation

> US National Institutes of Health, RePORTER application 10812234, Allosteric Modulation of the CB1 Receptor (5R01AA030509-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10812234. Licensed CC0.

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