Quercetin 3,7-dimethyl ether: a vasorelaxant flavonoid isolated from Croton schiedeanus Schlecht.
The vasorelaxant profile of quercetin 3,7-dimethyl ether, a flavonoid isolated from Croton schiedeanus Schlecht (Euphorbiaceae), was assessed in aortic rings isolated from Wistar rats. To gain insight into its structure-activity relationship, we compared this substance with quercetin 3,4',7-trimethyl ether (ayanin), another flavonoid isolated from this plant, quercetin 3,3',4',7-tetramethyl ether, a flavonoid synthesized by us, and quercetin. In addition we examined the interaction of quercetin 3,7-dimethyl ether with the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. According to their pEC50 values (concentration producing a 50% inhibition of the maximal contractile response) to phenylephrine-induced precontraction in rat isolated aorta, the potency order was quercetin 3,7-dimethyl ether > quercetin > quercetin 3,4',7-trimethyl ether > quercetin 3,3',4',7-tetramethyl ether (4.70+/-0.18; 3.96+/-0.07; 3.64+/-0.02; 3.11+/-0.16). The relaxant effect of quercetin 3,7-dimethyl ether was significantly decreased by the removal of endothelium as well as by methylene blue, an inhibitor of guanylyl cyclase, and by N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME), an NO-synthase inhibitor. Therefore, quercetin 3,7-dimethyl ether has a NO/cGMP pathway-related profile, with increased vasorelaxant activity due to hydroxylation at positions 3 and 4 of the B ring. In addition, methylation at positions 3 and 7 with respect to quercetin of the C and A rings, respectively, seems to further enhance the vasorelaxant activity of quercetin 3,7-dimethyl ether.
Guerrero
M F
MF
Laboratorio de Farmacognosia y Farmacología, Facultad de Farmacia, Universidad de Salamanca, E-37007 Salamanca, Spain.
Puebla
P
P
Carrón
R
R
Martín
M L
ML
San Román
L
L
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D029802:Croton / Q000737:chemistry*; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011794:Quercetin / Q000031:analogs & derivatives / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000302:isolation & purification / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; C065497:3,7-dimethoxy-5,3',4'-trihydroxyflavone; D009569:Nitric Oxide; D011794:Quercetin; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester