RESUMO
The α4ß2 nAChR is the most predominant subtype in the brain and is a well-known culprit for nicotine addiction. Previously we presented a series of α4ß2 nAChR selective compounds that were discovered from a mixture-based positional-scanning combinatorial library. Here we report further optimization identified highly potent and selective α4ß2 nAChR antagonists 5 (AP-202) and 13 (AP-211). Both compounds are devoid of in vitro agonist activity and are potent inhibitors of epibatidine-induced changes in membrane potential in cells containing α4ß2 nAChR, with IC50 values of approximately 10 nM, but are weak agonists in cells containing α3ß4 nAChR. In vivo studies show that 5 can significantly reduce operant nicotine self-administration and nicotine relapse-like behavior in rats at doses of 0.3 and 1 mg/kg. The pharmacokinetic data also indicate that 5, via sc administration, is rapidly absorbed into the blood, reaching maximal concentration within 10 min with a half-life of less than 1 h.
Assuntos
Nicotina/administração & dosagem , Antagonistas Nicotínicos/química , Antagonistas Nicotínicos/farmacologia , Receptores Nicotínicos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Comportamento de Procura de Droga/efeitos dos fármacos , Masculino , Antagonistas Nicotínicos/farmacocinética , Ratos Sprague-Dawley , Receptores Nicotínicos/metabolismo , Reforço Psicológico , Autoadministração , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Pioglitazone is a selective peroxisome proliferator-activated receptor γ (PPARγ) agonist used for the treatment of insulin resistance and type 2 diabetes. Previous studies conducted in our laboratory showed that activation of PPARγ by pioglitazone reduces alcohol drinking, stress-induced relapse, and alcohol withdrawal syndrome in rats. Pioglitazone was not able to prevent relapse elicited by alcohol cues. Conversely, the nonselective opioid antagonist naltrexone has been shown to reduce alcohol drinking and cue- but not stress-induced relapse in rodents. METHODS: Based on these findings, this study was sought to determine the efficacy of pioglitazone and naltrexone combination on alcohol intake and relapse behavior. Genetically selected alcohol-preferring Marchigian Sardinian (msP) rats were used for the study. RESULTS: Pioglitazone (10 and 30 mg/kg) and naltrexone (0.25 and 1.0 mg/kg) each individually reduced alcohol drinking in msP rats. The combination of the 2 drugs resulted in a more potent alcohol drinking reduction than single agents. Confirming previous studies, pioglitazone (10 and 30 mg/kg) significantly reduced relapse induced by the pharmacological stressor yohimbine (1.25 mg/kg) but not by cues predictive of alcohol availability. Conversely, naltrexone reduced reinstatement of drug seeking elicited by alcohol cues but not by yohimbine. CONCLUSIONS: The drug combination was effective in reducing both relapse behaviors. These findings open new vistas in the use pioglitazone in combination with naltrexone for the treatment of alcoholism.
Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , PPAR gama/metabolismo , Tiazolidinedionas/uso terapêutico , Animais , Sinais (Psicologia) , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Hipoglicemiantes/farmacologia , Masculino , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Pioglitazona , Ratos , Tiazolidinedionas/farmacologia , IoimbinaRESUMO
For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.
Assuntos
Moduladores de Receptores de Canabinoides , Canabinoides/farmacologia , Canabinoides/toxicidade , Doenças do Sistema Nervoso Central/tratamento farmacológico , Endocanabinoides , Animais , Moduladores de Receptores de Canabinoides/efeitos adversos , Moduladores de Receptores de Canabinoides/agonistas , Moduladores de Receptores de Canabinoides/uso terapêutico , Cannabis , Humanos , Aprendizagem/efeitos dos fármacos , Abuso de Maconha/fisiopatologia , Patentes como Assunto , Fitoterapia , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismoRESUMO
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.
Assuntos
Fármacos Antiobesidade/farmacologia , Antagonistas de Receptores de Canabinoides , Triazóis/farmacologia , Animais , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Agonistas de Receptores de Canabinoides , Cicloexanos/farmacologia , Cicloexanóis , Ingestão de Alimentos/efeitos dos fármacos , Etanol/administração & dosagem , Comportamento Alimentar/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Membranas Artificiais , Atividade Motora/efeitos dos fármacos , Permeabilidade , Fenóis/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Ratos Zucker , Rimonabanto , Autoadministração , Triazóis/efeitos adversos , Triazóis/metabolismoRESUMO
BACKGROUND: Hypericum perforatum extracts attenuate ethanol intake in alcohol-preferring rats. The opioid receptor antagonists, naloxone and naltrexone, reduce ethanol intake in rats and humans. The combination of different agents that reduce ethanol intake has been proposed as an approach to the pharmacotherapy of alcoholism. This study evaluated the effect on ethanol intake of the combined administration of a CO2 H. perforatum extract and naloxone or naltrexone in genetically selected Marchigian Sardinian alcohol-preferring rats. METHODS: Ten percent (v/v) ethanol intake was offered 2 hr per day at the beginning of the dark phase of the reverse light-dark cycle. H. perforatum CO2 extract was given intragastrically, 1 hr before access to ethanol. Naloxone or naltrexone was given by intraperitoneal injection 10 min before the extract. RESULTS: H. perforatum CO2 extract reduced ethanol intake at 31 or 125 mg/kg, but not 7 mg/kg. These doses neither modified food or water intake during access to ethanol, nor reduce 0.2% saccharin intake. Naloxone reduced ethanol and food intake at 3 or 5 mg/kg, but not 1 mg/kg. When naloxone 1 mg/kg was combined with the three doses of H. perforatum CO2 extract, the attenuation of ethanol intake was more pronounced than that observed after the administration of the extract alone. Alcohol intake was also significantly reduced by 7 mg/kg of H. perforatum CO2 extract combined with naloxone 1 mg/kg. The combined treatments never modified the rat's locomotor activity nor the simultaneous intake of food, water or 0.2% saccharin. Naltrexone reduced ethanol intake at 1 and 3 mg/kg, but not at 0.5 mg/kg. When naltrexone 0.5 mg/kg was combined with H. perforatum CO2 extract 7 mg/kg, ethanol intake was markedly reduced. CONCLUSIONS: These findings provide evidence that H. perforatum CO2 extract and opiate receptor antagonists act synergistically to induce a pronounced and selective reduction of voluntary ethanol consumption in alcohol-preferring rats.