Synthesis and Pharmacological Characterization of Novel Peripheral Cannabinoid‑1 Receptor Blockers Based on a Tricyclic Scaffold

The development of peripherally selective cannabinoid-1
receptor
(CB1R) antagonists offers a promising strategy for obesity
treatment. Here, we evaluated the efficacy of novel tricyclic CB1R antagonists, focusing on BNS808. Our findings demonstrate
that BNS808 exhibits robust CB1R antagonism with notable
CB2R selectivity, minimal brain penetration, and potent
in vitro and in vivo efficacy. The compound’s high plasma protein
binding reduces free drug availability for CNS entry, enhancing safety
and minimizing drug–drug interactions. In diet-induced obese
mice, BNS808 effectively reduced body weight, adiposity, liver triglycerides,
and liver enzymes, supporting its peripherally mediated action. These
results highlight BNS808 as a promising candidate for obesity treatment.
Additionally, our novel library of peripherally selective CB1R antagonists provides a strong foundation for future drug development.
With further refinement, BNS808 holds significant clinical potential
to address the global obesity epidemic.