RESUMO
A series of 1-methyl-5-(pyrazol-3- and -5-yl- and 1, 2, 4-triazol-3- and 5-yl)-1, 2, 3, 6-tetrahydropyridine derivatives structurally related to arecoline were synthesized and evaluated on M(1), M(2), and M(3) muscarinic receptors using [(3)H] pirenzepine and [(3)H] NMS as ligands. The binding affinity depended on the position and size of the substituents. The most interesting compounds were further evaluated in functional studies on isolated organs and in vivo for cholinergic side effects. Compounds 5 l and 6 i good M(1) and M(3) antagonistic properties in vitro and were devoid of cholinergic side effects in vivo.
Assuntos
Colinérgicos/síntese química , Pirazóis/síntese química , Piridinas/síntese química , Receptores Muscarínicos/efeitos dos fármacos , Triazóis/síntese química , Animais , Atropina/farmacologia , Ligação Competitiva , Colinérgicos/química , Colinérgicos/farmacologia , Cobaias , Íleo/efeitos dos fármacos , Técnicas In Vitro , Ligantes , Masculino , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Especificidade de Órgãos , Oxotremorina/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Coelhos , Relação Estrutura-Atividade , Suínos , Triazóis/química , Triazóis/farmacologia , Bexiga Urinária/efeitos dos fármacos , Ducto Deferente/efeitos dos fármacosRESUMO
In order to develop new cholinesterase agents effective against Alzheimer's disease (AD) we synthesized some phenylcarbamates structurally related to Rivastigmine and evaluated their in vitro and in vivo biological activity. Among the compounds which displayed the most significant in vitro activity, 1-[1-(3-dimethylcarbamoyloxyphenyl)ethyl]piperidine (31b), in addition to a simple and cheaper synthesis, showed lower toxicity and very similar therapeutic index in comparison with Rivastigmine.
