RESUMO
The preparation and structure-activity relationships of a series of 2-amino-alpha-thienylbenzeneethanamines are described. From this work, (+/-)-2-amino-N-methyl-alpha-(3-methyl-2-thienyl)-benzeneethanamine++ + (3a) and the homologous N-ethyl analog 3b emerged as novel noncompetitive NMDA antagonists with neuroprotective properties. Optical resolution of 3a and X-ray crystallography of (+)3a were performed. The racemate and enantiomers were evaluated for neuroprotective properties in models of ischemia-induced hippocampal damage (gerbil) and cerebral focal ischemia (rat). Pretreatment with 3a, (+)3a, or (-)3a significantly reduced ischemia-induced CA1 hippocampal damage. Posttreatment with 3a afforded a lower degree of neuroprotection. A highly significant reduction in infarct volume was observed with 3a in the cerebral focal ischemia model, with only weak positive effects being displayed by (+)3a. Dose-limiting side effects were associated with all three compounds in this model. In summary, the results demonstrate the utility of noncompetitive NMDA antagonists as neuroprotective agents for ischemia-induced neurodegeneration.
Assuntos
Compostos de Anilina/síntese química , Compostos de Anilina/uso terapêutico , N-Metilaspartato/antagonistas & inibidores , Tiofenos/síntese química , Tiofenos/uso terapêutico , Compostos de Anilina/química , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Ansiolíticos/uso terapêutico , Anticonvulsivantes/síntese química , Anticonvulsivantes/uso terapêutico , Ligação Competitiva , Isquemia Encefálica/prevenção & controle , Infarto Cerebral/prevenção & controle , Cristalografia por Raios X , Modelos Animais de Doenças , Gerbillinae , Hipocampo/irrigação sanguínea , Hipocampo/efeitos dos fármacos , Isomerismo , Masculino , Camundongos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade , Tiofenos/químicaRESUMO
External Ca2+-ions as well as certain xanthine derivatives are known to influence red blood cell properties. Therefore interaction of some xanthine derivatives with Ca-salts have been examined in vitro. Synthesis of five Ca-xanthine derivative complexes is described. The ability of complexing Ca2+-ions gives an insight into the probable mode of action of certain xanthine drugs.
