Various preparations of digitalis are used widely as oral cardiotonic agents. Their major disadvantage is the difficulty in selection of the proper dose to produce the desired therapeutic effect. Their safety margin, a ratio of the dose producing positive inotropic effect to that causing an adverse reaction, such as arrhythmia, is narrow.Catecholamines represent the alternative therapy of heart failure. Unlike digitalis, they can be given only intravenously. They have many pharmacological properties other than positive inotropic. When catecholamines are used as cardiotonic agents, these properties determine their side effects. Catecholamines also have arrhythmogenic properties, and long-term therapy with catecholamines can lead to the development of tolerance. Dopamine and dobutamine have less adverse effects than other catecholamines and are often used clinically. They are, however, not entirely selective as positive inotropic agents. Dopamine has a-adrenergic agonist and dobutamine has a-and &adrenergic agonist effects.Structure-activity relationship studies with trimetoquinol, a &selective agonist, led to the discovery of denopamine (Fig. 1). It is a partial agonist with a highly selective pi component of action.Pharmacological studies showed that denopamine had no a-and almost no p2-adrenergic agonist effects, but is the most selective pi -adrenoceptor agonist ever reported. The electrophysiological and biochemical studies with denopamine helped to differentiate denopamine from catecholamines. Denopamine is active orally and produces less increase in Ca influx and in cardiac CAMP levels than catecholamines. It produces long-lasting positive inotropic effect at doses that have no effect on arterial pressure; it has only weak positive chronotropic effect and little effect on myocardial oxygen consumption. Its arrhythmogenic effect is weak. Its long-term administration does not lead to the development of tolerance.
CHEMISTRYThe chemical name of denopamine, known previously as TA-064, is (-)-(I?)-1 -Cphydroxypheny1)-2-[( 3,4-dimethoxyphenethyl)amino]ethanol. It was synthesized at
