Summary
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 α1-adrenoceptor agonist activity in isolated guinea pig aorta. However, both enantiomers of 3-O-methyldobutamine were competitive α1-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 3H-prazosin binding from α1-adrenoceptors in rat cerebral cortex. The α1-adrenoceptor blocking activity of (+)-3-O-methyldobutamine was relatively potent and corresponded to a pA2 of 7.33 in guinea pig aorta and a-log K i of 7.72 in radioligand binding studies. Neither enantiomer of 3-O-methyldobutamine possessed α2-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 α2-adrenoceptor antagonist, yohimbine, and was found to result from weak anticholinergic activity (pA2=5.06). Neither enantiomer of 3-O-methyldobutamine possessed β1-adrenoceptor agonist activity in guinea pig atria, however the (+)-enantiomer was a weak noncompetitive antagonist at β1-adrenoceptors. In contrast, both enantiomers of 3-O-methyldobutamine were weak β2-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 α1-adrenoceptor antagonist, with minimal activity at α2-, β1- and β2-adrenoceptors. It is hypothesized that the potent α1-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.
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Ruffolo, R.R., Messick, K. & Horng, J.S. Interactions of the enantiomers of 3-O-methyldobutamine with α- and β-adrenoceptors in vitro. Naunyn-Schmiedeberg's Arch. Pharmacol. 329, 244–252 (1985). https://doi.org/10.1007/BF00501875
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DOI: https://doi.org/10.1007/BF00501875