Structure–activity relationship of wedelolactone analogues: Structural requirements for inhibition of Na+,K+-ATPase and binding to the central benzodiazepine receptor

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.

Wedelolactone and nine coumestan analogues were synthesized and a structure–activity relationship performed for their effect as inhibitors of kidney Na+,K+-ATPase and ligands for the central benzodiazepine receptor.Figure optionsDownload as PowerPoint slide