| Abstrakt: |
The enantiomers of 3-O-methyldobutamine, a metabolite of dobutamine, were evaluated for their α- and β-adrenoceptor mediated effects in vitro in a variety of isolated organs and in radioligand binding studies. Neither enantiomer of 3-O-methyldobutamine possessed α-adrenoceptor agonist activity in isolated guinea pig aorta. However, both enantiomers of 3-O-methyldobutamine were competitive α-adrenoceptor antagonists, with the (+)-enantiomer being approximately 10-fold more potent than the (-)-enantiomer as assessed either in guinea pig aorta or by displacement of H-prazosin binding from α-adrenoceptors in rat cerebral cortex. The α-adrenoceptor blocking activity of (+)-3-O-methyldobutamine was relatively potent and corresponded to a pA of 7.33 in guinea pig aorta and a-log K of 7.72 in radioligand binding studies. Neither enantiomer of 3-O-methyldobutamine possessed α-adrenoceptor agonist activity in field-stimulated guinea pig ileum. Although (+)-3-O-methyldobutamine weakly inhibited the twitch response in field-stimulated guinea pig ileum, the response was not blocked by the selective α-adrenoceptor antagonist, yohimbine, and was found to result from weak anticholinergic activity (pA=5.06). Neither enantiomer of 3-O-methyldobutamine possessed β-adrenoceptor agonist activity in guinea pig atria, however the (+)-enantiomer was a weak noncompetitive antagonist at β-adrenoceptors. In contrast, both enantiomers of 3-O-methyldobutamine were weak β-adrenoceptor agonists in rat uterus, however these weak effects were not highly stereoselective, which was also confirmed in radioligand binding studies. The results of the present study indicate that 3-O-methyldobutamine is a potent and highly selective α-adrenoceptor antagonist, with minimal activity at α-, β- and β-adrenoceptors. It is hypothesized that the potent α-adrenoceptor antagonist activity of 3-O-methyldobutamine, which resides predominantly in the (+)-enantiomer, may play a role in the hemodynamic effects of dobutamine, by contributing, in part, to the decrease in total peripheral vascular resistance observed following administration of dobutamine. [ABSTRACT FROM AUTHOR] |
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