RESUMO
Recent studies have suggested that the alpha7 nicotinic acetylcholine receptors play important roles in learning and memory. Herein, we describe our research of the structure-activity relationships (SAR) in a series of (S)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-ones bearing various bicyclic moieties to discover novel alpha7 receptor agonists. Through a number of SAR studies on the series, we have found out that inhibition of CYP 2D6 isozyme, which was a primary obstacle for the previously identified compound, was avoidable by the introduction of bicyclic moieties. Chemical optimization of the series led to the identification of a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist 23. This compound not only possessed high binding affinity (K(i) = 3 nmol/L) toward the alpha7 receptor but also showed agonistic activity even at a concentration of 0.1 micromol/L. In addition, compound 23 improved cognition in several rat models, which might suggest the potential of the alpha7 receptor partial agonist for the treatment of neurological disorders including cognitive dysfunction.
Assuntos
Cognição/efeitos dos fármacos , Agonistas Nicotínicos/síntese química , Nootrópicos/síntese química , Oxazóis/síntese química , Quinuclidinas/síntese química , Receptores Nicotínicos/metabolismo , Animais , Disponibilidade Biológica , Córtex Cerebral/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Dopamina/metabolismo , Potenciais Evocados Auditivos/efeitos dos fármacos , Haplorrinos , Hipocampo/metabolismo , Técnicas In Vitro , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Agonistas Nicotínicos/farmacocinética , Agonistas Nicotínicos/farmacologia , Nootrópicos/farmacocinética , Nootrópicos/farmacologia , Oxazóis/farmacocinética , Oxazóis/farmacologia , Técnicas de Patch-Clamp , Quinuclidinas/farmacocinética , Quinuclidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores Nicotínicos/fisiologia , Estereoisomerismo , Relação Estrutura-Atividade , Receptor Nicotínico de Acetilcolina alfa7RESUMO
The effect of Y-931 (8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine maleate), a novel potential atypical antipsychotic candidate, in producing dystonia in Cebus monkeys was investigated. Y-931 induced relatively weak dystonia in several observation periods at doses greater than 0.1 mg/kg, i.m. Although Y-931 significantly increased total dystonia scores (the sum of 15 to 360 min after injection) at doses greater than 0.5 mg/kg, i.m., the scores did not exceed 20, up to a dose of 1.0 mg/kg, i.m. and lacked a dose-response relationship. The present result suggests that Y-931 is predicted to have a low risk of extrapyramidal side effects.