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.
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.
Pavon
Francisco Javier
FJ
Fundación IMABIS, Neuropharmacology, Hospital Carlos Haya, Avenida Carlos Haya 82, 7(a) Planta, Pabellón A, Málaga 29010, Spain.
Bilbao
Ainhoa
A
Hernández-Folgado
Laura
L
Cippitelli
Andrea
A
Jagerovic
Nadine
N
Abellán
Gumersindo
G
Rodríguez-Franco
M A Isabel
MA
Serrano
Antonia
A
Macias
Manuel
M
Gómez
Raquel
R
Navarro
Miguel
M
Goya
Pilar
P
Rodríguez de Fonseca
Fernando
F
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*
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