RESUMO
Muscarinic agonists might be useful in the treatment of neurological disorders, including Alzheimer's disease, schizophrenia, chronic pain, and drug abuse. Previous studies identified a series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine with high activity and selectivity for muscarinic receptors. To develop compounds with improved central nervous system penetration, several new derivatives were synthesized and characterized for muscarinic receptor binding and activity. One ligand (11) exhibited agonist activity at M(1), M(2), and M(4) receptors, a selectivity profile suggesting potential utility in the treatment of schizophrenia.
Assuntos
Agonistas Muscarínicos/síntese química , Agonistas Muscarínicos/farmacologia , Doenças do Sistema Nervoso/tratamento farmacológico , Piridinas/síntese química , Piridinas/farmacologia , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Animais , Benzilatos/antagonistas & inibidores , Benzilatos/química , Ligação Competitiva , Células CHO , Carbacol/farmacologia , Linhagem Celular , Colforsina/antagonistas & inibidores , Colforsina/farmacologia , Cricetinae , AMP Cíclico/metabolismo , Humanos , Hipotermia/induzido quimicamente , Masculino , Camundongos , Modelos Moleculares , Agonistas Muscarínicos/metabolismo , Piridinas/química , Piridinas/metabolismo , Ensaio Radioligante , Ratos , Ratos Long-Evans , Receptores Muscarínicos/metabolismo , Tiadiazóis/química , Tiadiazóis/metabolismoRESUMO
Ring-opening alkoxycarbonylation of epoxy-steroids has been carried out with a Co2(CO)8/3-hydroxypyridine catalytic system. High chemo- and regioselectivities were obtained under the reaction conditions applied. Structural analysis of the products proved their high stereochemical purity in each case, accompanied by inversion of the original configuration. No carbonylation took place for sterically hindered steranic epoxides.