Inotropic effects of 5-hydroxy auranetin and its semi-synthetic derivatives

In the Indian system of medicine, Citrus aurantium Linn. (family: Rutaceae) has been used to treat stomach ache, hypertension, megalospleny, menorrhagia. C. aurantium and extracts of its dried fruits and peels have been used for years in traditional Western medicines. An active principle, N-Methyltyramine of C. aurantium has been reported for its positive inotropic effect on rabbit heart [1]. Nevertheless very little is known regarding the polymethoxylated flavone of C. aurantium, 5-hydroxy auranetin. The aim of the present study was to investigate the inotropic effects of 5-hydroxy auranetin and its semi-synthetic derivatives on isolated frog heart [2]. 5-hydroxy auranetin (5-hydroxy-3,6,7,8,4'-pentamethoxyflavone) (A) was isolated from the petroleum ether extract of C. aurantium peels [3]. Derivatives of 5-hydroxy auranetin include benzoylated (B) and acetylated (C) compounds. All these compounds were characterized by spectral analyses. Compounds A and C showed an initial negative inotropic effect followed by positive effect at 4.0µg/mL and 6.0µg/mL concentrations respectively thereby indicating biphasic response. Compound B exhibited significant positive inotropic effect at 1.5µg/mL concentration (p<0.05) and also showed a synergistic action when administrated simultaneously with adrenaline (10µg/mL), suggesting a possible direct agonist action on β-adrenoceptor. This effect could be attributed to the presence of benzoyl group and this investigation has demonstrated compound B to be a novel flavone correlating its cardiac activity with that of β-adrenoceptor-mediated positive inotropic effect.

Fig.1: Structures

Acknowledgements: We thank Dr. Usman Ali for authentifying the plant material, C. aurantium.

References: 1. Xiu, C. et al. (1981) Acta Pharm. Sci. 16: 253–259.

2. Kulkarni SK. (1999) Handbook of Experimental Pharmacology. Vallabh Prakashan. Delhi.

3. Sarin, PS., Seshadri, TR. (1960) Tetrahedron 8: 64–66.