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1.
Org Biomol Chem ; 13(43): 10705-15, 2015 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-26349488

RESUMEN

A novel two step protocol was developed to gain regiospecific access to 3-substituted ß- and aza-ß-carbolines, 3-PBC (1), 3-ISOPBC (2), ßCCt (3), 6-aza-3-PBC (4) and 6-aza-3-ISOPBC (5). These ß-carbolines (1-3) are potential clinical agents to reduce alcohol self-administration, especially 3-ISOPBC·HCl (2·HCl) which appears to be a potent anti-alcohol agent active against binge drinking in a rat model of maternally deprived (MD) rats. The method consists of two consecutive palladium-catalyzed reactions: a Buchwald-Hartwig amination followed by an intramolecular Heck-type cyclization in high yield.


Asunto(s)
Alcoholismo/tratamiento farmacológico , Compuestos Aza/síntesis química , Carbolinas/síntesis química , Paladio/química , Animales , Compuestos Aza/química , Compuestos Aza/uso terapéutico , Consumo Excesivo de Bebidas Alcohólicas/tratamiento farmacológico , Carbolinas/química , Carbolinas/uso terapéutico , Catálisis , Modelos Moleculares , Ratas , Estereoisomerismo
2.
Alcohol Clin Exp Res ; 38(4): 1108-17, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24330519

RESUMEN

BACKGROUND: Alcohol potentiates GABAergic neurotransmission via action at the GABAA receptor. α1 subunit-containing GABAA receptors have been implicated as mediators, in part, of the behavioral and abuse-related effects of alcohol in rodents. METHODS: We systematically investigated the effects of 1 α1-preferring benzodiazepine agonist, zolpidem, and 2 antagonists, ß-carboline-3-carboxylate-tert-butyl ester (ßCCT) and 3-propoxy-ß-carboline hydrochloride (3-PBC), on oral self-administration of alcohol (2% w/v) or sucrose solution and observable behavior in rhesus macaques. We compared these effects to those of the nonselective benzodiazepine agonist triazolam, antagonist flumazenil, and inverse agonist ß-carboline carboxylate (ßCCE). RESULTS: Alcohol and sucrose solutions maintained reliable baseline drinking behavior across the study. The α1-preferring compounds did not affect intake, number of sipper extensions, or blood alcohol levels (BALs) at any of the doses tested. Zolpidem, ßCCT, and 3-PBC increased latency to first sipper extension in animals self-administering alcohol, but not sucrose, solution. Triazolam exerted biphasic effects on alcohol-drinking behavior, increasing intake at low doses but decreasing BAL and increasing latency at higher doses. At doses higher than those effective in alcohol-drinking animals, triazolam increased sucrose intake and latency. Flumazenil nonsystematically increased number of extensions for alcohol but decreased BAL, with no effects on sucrose drinking. ßCCE decreased sipper extensions for alcohol and increased latency for first sucrose sipper extension, but full dose-effect relationships could not be determined due to seizures at higher doses. CONCLUSIONS: Alcohol-drinking animals appeared more sensitive to the effects of GABAergic compounds on drinking behavior. However, these results do not support a strong contribution of α1GABAA receptors to the reinforcing effects of alcohol in primates.


Asunto(s)
Consumo de Bebidas Alcohólicas/psicología , Modelos Animales , Subunidades de Proteína/fisiología , Receptores de GABA-A/fisiología , Consumo de Bebidas Alcohólicas/prevención & control , Animales , Etanol/administración & dosificación , Agonistas de Receptores de GABA-A/farmacología , Agonistas de Receptores de GABA-A/uso terapéutico , Antagonistas de Receptores de GABA-A/farmacología , Antagonistas de Receptores de GABA-A/uso terapéutico , Macaca mulatta , Masculino , Subunidades de Proteína/agonistas , Subunidades de Proteína/antagonistas & inhibidores , Autoadministración
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