Interaction of the enantiomers of 3-0-methyldobutamine, a metabolite of dobutamine, with alpha- and beta-adrenoreceptors in the cardiovascular system of the pithed rat.

Abstract

The pharmacological activities of the enantiomers of 3-0-methyldobutamine, a metabolite of dobutamine, were investigated at alpha- and beta-adrenoreceptors in the cardiovascular system of pithed rats. Neither enantiomer of 3-0-methyldobutamine produced vasoconstriction in pithed rats, indicating a lack of alpha 1- or alpha 2-adrenoreceptor agonist activity. However, both enantiomers of 3-0-methyldobutamine were found to be alpha 1-adrenoreceptor antagonists. The alpha 1-adrenoreceptor antagonist activity of the enantiomers of 3-0-methyldobutamine was selective, since neither enantiomer antagonized alpha 2-adrenoreceptors at doses up to 10 mg/kg, i.v. The alpha 1-adrenoreceptor antagonist activity of (+)- and (-)-3-0-methyldobutamine was studied in detail in pithed rats. Based on a Schild analysis of the antagonism of the alpha 1-adrenoreceptor mediated pressor effects of cirazoline, (+)-3-0-methyldobutamine had a DR2 value (i.e., dose required to produce a two-fold rightward shift in the dose-response curve of cirazoline) of 0.16 mg/kg, i.v., whereas the DR2 value for (-)-3-0-methyldobutamine was 10.3 mg/kg, i.v. Thus, the potent alpha 1-adrenoreceptor antagonist activity of 3-0-methyldobutamine resides predominantly in the (+)-enantiomer, the latter being approximately 64-fold more potent than the (-)-enantiomer. Both enantiomers of 3-0-methyldobutamine were weak beta 1-adrenoreceptor antagonists that, at high doses, inhibited the chronotropic effect of isoprenaline. In addition, both enantiomers were weak beta 2-adrenoreceptor agonists that produced modest decreases in diastolic blood pressure at high doses. The beta 1-adrenoreceptor antagonist and the beta 2-adrenoreceptor agonist effects of the enantiomers of 3-0-methyldobutamine occurred at doses in excess of 3 mg/kg, i.v. attesting to their weak activity, and neither effect was stereoselective. It is hypothesized that of the potent alpha 1-adrenoreceptor blocking activity of 3-0-methyldobutamine, which resides predominantly in the (+)-enantiomer, may contribute, in part, to the reduction in total peripheral vascular resistance observed following infusion of dobutamine.