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
| Autor: | Francisco Javier Pavón, Laura Hernandez-Folgado, Gumersindo Abellán, Fernando Rodríguez de Fonseca, Pilar Goya, Andrea Cippitelli, Raquel Gómez, Ainhoa Bilbao, M. Isabel Rodríguez-Franco, Nadine Jagerovic, Manuel Macias, Antonia Serrano, Miguel Navarro |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Cannabinoid receptor medicine.medical_treatment Self Administration Pharmacology Eating Rimonabant Piperidines Food intake Chemistry Self-administration Brain Cannabinoid Receptor Agonists Blood-Brain Barrier SR141716A Alcohol medicine.drug Agonist medicine.medical_specialty medicine.drug_class Motor Activity Permeability Cellular and Molecular Neuroscience Phenols Cyclohexanes Internal medicine medicine Inverse agonist Animals Rats Wistar Maze Learning Cannabinoid Cannabinoid Receptor Antagonists Ethanol Antagonist Membranes Artificial Feeding Behavior Triazoles Cyclohexanols Rats Rats Zucker Endocrinology Cannabinoid receptor antagonist Rat Pyrazoles Anti-Obesity Agents |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 0028-3908 |
| Popis: | 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 bloodebrain 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. This work has been supported by The European 5th Framework Programme, grants QLRT-2001-01048 (TargAlc) and QLRT-2000-01691, MEC SAF 2004/07762, MEC SAF 2003/ 08003/C02, MEC SAF 2003/02262, Plan Nacional Sobre Drogas, FIS 02/001, Redes C03/06, C03/08, G03/028 and G03/05. L. H.-F. is recipient of I3P fellowship from the C.S.I.C. |
| Databáze: | OpenAIRE |
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