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

Abstract

Cannabinoid CB(1) 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 CB(1) antagonist/CB(2) 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 CB(1)-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 CB(1) antagonists devoid of central side effects.

• Authors: Jesse LoVerme, Andrea Duranti, Andrea Tontini, Gilberto Spadoni, Marco Mor, Silvia Rivara, Nephi Stella, Cong Xu, Giorgio Tarzia, Daniele Piomelli
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 3 Pg. 639-43 (Feb 01 2009) ISSN: 1464-3405 [Electronic] England
• PMID: 19128970 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (4-amino-1-(4-chlorobenzyl)-2-methyl-5-phenyl-1H-pyrrol-3-yl)(phenyl)methanone
• Anti-Obesity Agents
• Benzyl Compounds
• Cannabinoids
• Pyrroles
• Receptors, Cannabinoid

Topics

• Animals
• Anti-Obesity Agents (pharmacology)
• Benzyl Compounds (chemical synthesis, pharmacology)
• Body Weight
• Cannabinoids (antagonists & inhibitors, chemistry)
• Cerebellum (metabolism)
• Chemistry, Pharmaceutical (methods)
• Drug Design
• Feeding Behavior (drug effects)
• Humans
• Inhibitory Concentration 50
• Mice
• Models, Chemical
• Pyrroles (chemical synthesis, pharmacology)
• Rats
• Receptors, Cannabinoid (metabolism)
• Weight Gain (drug effects)