RESUMO
Ischemic stroke is one of the most severe brain pathologies that is extremely difficult to treat. Recently it has been found that acidosis accompanying cerebral ischemia induces activation of acid-sensing ion channel ASIC1a which results in its turn in the neuronal death. Here we present novel derivatives of 3-carboxamidinocoumarines that effectively inhibit ASIC1a and ASIC3 channels in concentration-dependent manner. The most active compound inhibits ASIC1a and ASIC3 channels with corresponding IC50 of 7.3 and 13.2 microM. Our data suggest that 3-carboxamidinocoumarines can be used as a scaffold for novel type of highly efficient anti-ischemic drugs.
Assuntos
Benzoatos/síntese química , Benzopiranos/síntese química , Desenho de Fármacos , Guanidinas/síntese química , Proteínas do Tecido Nervoso/antagonistas & inibidores , Canais Iônicos Sensíveis a Ácido , Potenciais de Ação/efeitos dos fármacos , Animais , Benzoatos/química , Benzoatos/farmacologia , Benzopiranos/química , Benzopiranos/farmacologia , Relação Dose-Resposta a Droga , Gânglios Espinais/citologia , Guanidinas/química , Guanidinas/farmacologia , Células HEK293 , Humanos , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Canais de SódioRESUMO
Almost each natural venom comprises a considerable combinatorial library of bioactive substances that have been optimized during evolution. Particular attention is devoted currently on a search for new modulators of ion channels from the venoms of arthropods. We have studied the effect of peptidous compounds of the Lycosa spider venom on the activity of P2X receptors in DRG neurons of rats. As a result, at least 7 proteins modulating various P2X receptor-operated ionic currents in the sensory neurons of rats have been found.
