Synthetic CB1 Modulators in Clinical Trials: A Medicinal Chemistry Review

Area of Science:

• Medicinal Chemistry
• Neuropharmacology
• Endocannabinoid System Research

Background:

• The endocannabinoid system (ECS) regulates vital functions, but CB1 receptor modulation faces challenges due to central adverse effects.
• Limited clinical translation of ECS therapeutics, with only dronabinol and nabilone approved, underscores the need for safer modulators.

Purpose of the Study:

• To review synthetic small-molecule CB1 receptor modulators that have progressed to clinical trials from a medicinal chemistry viewpoint.
• To analyze structure-activity relationships and identify design strategies for safer CB1 modulators.

Main Methods:

• Review of nine synthetic CB1 modulators (agonists and antagonists) in clinical trials for diverse indications.
• Comparative structure-activity relationship analysis of 189 molecules across different chemical classes.

Main Results:

• CB1 modulators are being explored for autism spectrum disorder, neuropathic pain, osteoarthritis, obesity, and cognitive impairment.
• Agonists often lack CB1/CB2 selectivity, while antagonists more readily achieve CB1 selectivity.
• Recurrent design strategies involve modifications in lateral chains and tail domains.

Conclusions:

• Central nervous system adverse effects remain a key hurdle, driving research into peripherally restricted and biased modulators.
• Integrating structural, pharmacological, and clinical data is crucial for designing safer and more effective CB1 receptor modulators.