Synthetic CB1 modulators in clinical trials ; a medicinal chemistry perspective

INTRODUCTION: The endocannabinoid system includes CB1 and CB2 receptors, endocannabinoids, and the enzymes responsible for their synthesis and degradation. It regulates processes such as appetite, energy balance, nausea, immune responses, and neuroprotection. Despite its therapeutic potential, only two synthetic cannabinoids, Dronabinol and Nabilone, have been FDA-approved since the 1980s, and progress has been limited due to central adverse effects associated with CB1 modulation.

Objective

This work aimed to review the modulation of the CB1 receptor by synthetic compounds investigated in clinical trials, focusing on structural and functional trends from a medicinal chemistry perspective and performing a comparative structure-activity relationship (SAR) analysis.

Methods

Information on CB1 receptor modulators was retrieved from ClinicalTrials.gov, GlobalData, PubMed, SciFinder, and Google Scholar. Inclusion criteria were small synthetic molecules with known structures that reached at least Phase I clinical trials. Data on chemical modifications, pharmacokinetic and pharmacodynamic features, efficacy, and safety were collected for analysis.

Results

Nine synthetic molecules were identified: agonists ART-27.13, CMX-020, Dronabinol, HU-444, Nabilone, and antagonists AEF-0117, AEF-0217, Monlunabant, and Selonabant. These compounds are under investigation for indications such as autism spectrum disorder, neuropathic pain, osteoarthritis, obesity, acute cannabinoid intoxication, and cognitive impairment in Down syndrome. From the collected data, a SAR analysis was performed, encompassing 189 molecules. This revealed common strategies, such as modifications in the lateral chains of classical and non-classical cannabinoids and in the tail region of endocannabinoid analogs. Agonists typically showed limited CB1/CB2 selectivity, while antagonists displayed higher CB1||selectivity. The main challenge remains central nervous system adverse effects, which research seeks to mitigate through peripherally restricted ligands, biased signaling, and improved metabolic stability.

Conclusion

Despite the persistent challenge of central nervous system adverse effects, the knowledge derived from this review and SAR analysis offers useful guidance for medicinal chemistry. Structural parallels identified across different classes suggest that insights from one scaffold can inform the design of others. Continued integration of structural, pharmacological, and clinical data will be key to developing safer and more effective CB1 modulators