Synthesis and characterization of a peripherally restricted CB1 cannabinoid antagonist, URB447, that reduces feeding and body-weight gain in mice

Cannabinoid CB1 receptor antagonists reduce body weight in rodents and humans, but their clinical utility as anti-obesity agents is limited by centrally mediated side effects. Here, we describe the first mixed CB1 antagonist/CB2 agonist, URB447 ([4-amino-1-(4-chlorobenzyl)-2-methyl-5-phenyl-1H-pyrrol-3-yl](phenyl)methanone), which lowers food intake and body-weight gain in mice without entering the brain or antagonizing central CB1-dependent responses. URB447 may provide a useful pharmacological tool for investigating the cannabinoid system, and might serve as a starting point for developing clinically viable CB1 antagonists devoid of central side effects.

Graphical abstractSynthesis and in vivo pharmacology of the first mixed CB1 antagonist/CB2 agonist, URB447, which reduces food intake in rats with a peripheral mechanism, are reported.Figure optionsDownload full-size imageDownload as PowerPoint slide