RESUMO
3,5-Bicyclic aryl piperidines are a new class of high-affinity alpha4beta2 nicotinic receptor agents. We have sought nicotinic receptor partial agonists of the alpha4beta2 nicotinic acetylcholine receptor for smoking cessation, and a number of compounds fulfill potency, selectivity, and efficacy requirements in vitro. In vivo, selected agents demonstrate potent partial agonist efficacy on the mesolimbic dopamine system, a key measure of therapeutic potential for smoking cessation.
Assuntos
Piperidinas/química , Piperidinas/farmacologia , Receptores Nicotínicos/metabolismo , Abandono do Hábito de Fumar/métodos , Animais , Ciclização , Estrutura Molecular , Piperidinas/classificação , Ratos , Relação Estrutura-AtividadeRESUMO
Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.
Assuntos
Benzazepinas/síntese química , Agonistas Nicotínicos/síntese química , Quinoxalinas/síntese química , Receptores Nicotínicos/efeitos dos fármacos , Abandono do Hábito de Fumar/métodos , Animais , Benzazepinas/química , Benzazepinas/farmacologia , Linhagem Celular , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Humanos , Técnicas In Vitro , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Ensaio Radioligante , Ratos , Receptores Nicotínicos/fisiologia , Vareniclina , Xenopus laevisRESUMO
The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.