RESUMO
The molecular mechanisms involved in Na+,K+-ATPase inhibition by 2-methoxy-3,8,9-trihydroxy coumestan were investigated. We show that this compound decreases the free sulfydryl groups present in the enzyme and that its inhibitory effect is prevented by dithiothreitol and other two sulfydryl containing reagents. We propose a redox cycle culminating with the irreversible oxidation of sulfydryl groups essential for the catalytic activity of this enzyme and of two other related P-type ATPases.
Assuntos
Anticoagulantes/farmacologia , Cumarínicos/farmacologia , Inibidores Enzimáticos/farmacologia , Isoflavonas/farmacologia , Rim/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Animais , ATPase de Ca(2+) e Mg(2+)/antagonistas & inibidores , ATPase de Ca(2+) e Mg(2+)/metabolismo , Domínio Catalítico , Ditiotreitol/química , Ditiotreitol/metabolismo , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Rim/enzimologia , Oxirredução , Inibidores da Bomba de Prótons , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/metabolismo , Compostos de Sulfidrila/química , Compostos de Sulfidrila/metabolismoRESUMO
Coumestans 2a-i, bearing different patterns of substitution in A- and D-rings, were synthesized and evaluated as inhibitors of kidney Na+, K+ -ATPase and ligands for the central benzodiazepine (BZP) receptor. The presence of a hydroxyl group in position 2 favours the effect on Na+, K+ -ATPase but decreases the affinity for the BZP receptor, allowing the design of more selective molecules than the natural wedelolactone. On the other hand, the presence of a catechol in ring D is important for the effect on both molecular targets.