Cardiovascular Effects of KM-13, a New, Orally Effective, Cardiotonic Sympathomimetic Amine

Dobutamineʼs chemical structure was modified to make it orally effective, while its pharmacological profile was preserved. Testing on anesthetized dogs showed that replacement of the para hydroxyl group with carboxyamide at the phenyl end of the molecule increased inotropic potency threefold, but it introduced pressor activity that spoiled the inotropic selective profile of dobutamine. However, shifting carboxyamide to the meta position avoided pressor activity and further enhanced inotropic potency to nine times that of dobutamine. When administered orally to conscious dogs, this compound, KM-13 (5 mg/kg), produced a sustained increase in left ventricular dP/dt with only immediate changes in heart rate; 10 mg/kg dobutamine was without cardiovascular effects. The (−) isomer of KM-13 contained twice the inotropic activity of the (+) isomer; in contrast, the (−) isomer had no effect on diastolic blood pressure, while the (+) isomer lowered blood pressure. The inotropic and chronotropic effects of dobutamine and KM-13 are both largely due to β-adrenergic stimulation as shown by propranolol blockade. In contrast to dobutamine, KM-13 is an agent that is active by either oral or buccal administration and has greater inotropic potency.