Discovery of a Peripherally Directed CB1 Receptor Antagonist That Restores Insulin Signaling in Adipocytes

Abstract The antagonism of cannabinoid 1 receptor (CB1R) signaling has demonstrated clinical efficacy in treating obesity, improving insulin resistance, enhancing cardiovascular health, and mitigating metabolic risk factors in humans. Despite these positive outcomes, the clinical use of rimonabant was limited by severe central nervous system adverse effects, which reduced interest in CB1R and hindered the exploration of new therapeutic opportunities. Selective targeting of peripheral CB1R represents a promising strategy to overcome these limitations, creating therapeutic opportunities not only for obesity and metabolic disorders but also for smoking and alcohol addiction. Herein, we report a library of 53 novel, potent, and subtype-selective CB1R antagonists bearing polar groups, designed through convergent Ugi-based synthetic pathways. This approach enabled the identification of key structure–activity relationship features within this series and the effective modulation of molecular properties governing blood–brain barrier permeability. Among the compounds evaluated, the piperazine-1-ium derivative 24a stands out as the first permanently charged CB1R antagonist, exhibiting nanomolar affinity (Ki = 115 nM) and high CB1R/CB2R selectivity with a favorable physicochemical profile consistent with peripheral restriction and limited blood-brain barrier penetration. Importantly, 24a exhibits robust functional activity in a biologically relevant model of metabolic dysfunction. In insulin-resistant, lipid-hypertrophied adipocytes, 24a restores insulin-stimulated Akt phosphorylation and significantly enhances lipolytic activity, with effects comparable or superior to those of rimonabant at equivalent concentrations. These findings establish 24a as a promising peripherally restricted CB1R antagonist with demonstrated functional efficacy in a metabolic disease-relevant cellular model.