Structure-activity relationship of cardiotonic flavonoids in guinea-pig papillary muscle

Sixteen flavonoids were tested for a positive inotropic effect (PIE) on gui nea-pig papillary muscle paced at 0.2 Hz in a Krebs-Henseleit solution at 3 0 degrees C. The structure-activity relationship was investigated by determ ining both the pD(2) value and the intrinsic activity in the case of ten fl avonols, three flavones, one flavanone and two catechins. Quercetin showed the most potent intrinsic activity, and produced the strongest inotropic re sponses among the 16 compounds. The relative order of potency of the tested flavonoids was quercetin > morin = kaempferol = HEPTA > luteolin = apigeni n > natsudaidain = fisetin = galangin. Those that did not produce any PIE w ere 3-hydroxyflavone, flavone, glycosides of quercetin (rutin and hyperin), flavanones (naringenin) and catechins. With respect to the essential flavo noid nucleus for PIE development, the presence of a hydroxy group at C-4', an alpha,beta-unsaturated ketone on the C-ring and a reasonable lipophilic moiety in the molecule are required. Pharmacological analyses suggest that there is a common mechanism for the PIE and it is cyclic AMP dependent. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.