Synthesis and characterization of a peripherally restricted CB1 cannabinoid antagonist, URB447, that reduces feeding and body-weight gain in mice.
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.
LoVerme
Jesse
J
Department of Pharmacology, 360 MedScience II, University of California, Irvine, CA 92697-4625, USA.
Duranti
Andrea
A
Tontini
Andrea
A
Spadoni
Gilberto
G
Mor
Marco
M
Rivara
Silvia
S
Stella
Nephi
N
Xu
Cong
C
Tarzia
Giorgio
G
Piomelli
Daniele
D
D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D001835:Body Weight; D002186:Cannabinoids / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002531:Cerebellum / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D005247:Feeding Behavior / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D043882:Receptors, Cannabinoid / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
C539875:(4-amino-1-(4-chlorobenzyl)-2-methyl-5-phenyl-1H-pyrrol-3-yl)(phenyl)methanone; D019440:Anti-Obesity Agents; D001593:Benzyl Compounds; D002186:Cannabinoids; D011758:Pyrroles; D043882:Receptors, Cannabinoid