title: Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole--LH 21.
abstract: The present study evaluates the pharmacological profile of the new neutral cannabinoid CB1 receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole -LH-21- on feeding behavior and alcohol self-administration in rats, two behaviors inhibited by cannabinoid CB1 receptor antagonists. Administration of LH-21 (0.03, 0.3 and 3 mg/kg) to food-deprived rats resulted in a dose-dependent inhibition of feeding. Subchronic administration of LH-21 reduced food intake and body weight gain in obese Zucker rats. Acute effects on feeding were not associated with anxiety-like behaviors, or induction of complex motor behaviors such as grooming or scratching sequences, usually observed after central administration of cannabinoid receptor blockers with inverse agonist properties. LH-21 did not markedly reduce alcohol self-administration (30% reduction observed only at a high dose of 10 mg/kg). This pharmacological pattern partially overlaps that of the reference cannabinoid CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, SR141716A, (0.3, 1 and 3 mg/kg) that reduced feeding and alcohol self-administration with similar efficacy. In vitro analysis of blood-brain barrier permeability using a parallel artificial membrane permeation assay demonstrated that LH-21 has lower permeation through membranes than SR141716A. That was confirmed in vivo by studies showing lower potency of peripherally injected LH-21 when compared to SR141716A to antagonize motor depression induced by intracerebroventricular administration of the CB1 agonist CP55,940. The neutral antagonist profile and the lower penetration into the brain of LH-21 favour this class of antagonists with respect to reference inverse agonists for the treatment of obesity because they potentially will display reduced side effects.
authors.affiliation: Fundación IMABIS, Neuropharmacology, Hospital Carlos Haya, Avenida Carlos Haya 82, 7(a) Planta, Pabellón A, Málaga 29010, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Pavon
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Bilbao
authors.forename: Laura
authors.initials: L
authors.lastname: Hernández-Folgado
authors.forename: Andrea
authors.initials: A
authors.lastname: Cippitelli
authors.forename: Nadine
authors.initials: N
authors.lastname: Jagerovic
authors.forename: Gumersindo
authors.initials: G
authors.lastname: Abellán
authors.forename: M A Isabel
authors.initials: MA
authors.lastname: Rodríguez-Franco
authors.forename: Antonia
authors.initials: A
authors.lastname: Serrano
authors.forename: Manuel
authors.initials: M
authors.lastname: Macias
authors.forename: Raquel
authors.initials: R
authors.lastname: Gómez
authors.forename: Miguel
authors.initials: M
authors.lastname: Navarro
authors.forename: Pilar
authors.initials: P
authors.lastname: Goya
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D003510:Cyclohexanes / Q000494:pharmacology; D003511:Cyclohexanols; D004435:Eating / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage; D005247:Feeding Behavior / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008567:Membranes, Artificial; D009043:Motor Activity / Q000187:drug effects; D010539:Permeability; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D000077285:Rimonabant; D012646:Self Administration; D014230:Triazoles / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C515162:5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole; D019440:Anti-Obesity Agents; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D003510:Cyclohexanes; D003511:Cyclohexanols; D008567:Membranes, Artificial; D010636:Phenols; D010880:Piperidines; D011720:Pyrazoles; D014230:Triazoles; D000431:Ethanol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant