Development of selective dopamine receptor agonists as novel cardiovascular drugs

Benzazepine and ergoline derivatives represent two chemical classes from which orally effective dopamine receptor agonists have been developed. The benzazepines SK&F 38393 and SK&F 82526 increase renal and mesenteric blood flow as a consequence of regional vasodilation mediated by vascular (DA₁) dopamine receptor stimulation. Renal vasodilation produced by acute administration of SK&F 38393 and SK&F 82526 is associated with variable diuresis and natriuresis, and minimal change in arterial blood pressure and cardiac rate. Pergolide and LY141865 are chemically related to ergoline and inhibit neurogenic release of norepinephrine by stimulating neuronal (DA₂) dopamine receptors. As a result of this action, pergolide and LY141865 produce generalized cardiovascular alterations that are characterized by reduced systemic vascular resistance, arterial blood pressure, and cardic rate. SK&F 38393 and pergolide lack beta receptor agonist activity, although each produces alpha receptor mediated vasoconstriction at or slightly above doses activating dopamine receptors. SK&F 82526, LY141865, and LY171555 (the levo enantiomer of LY141865) are more selective DA₁ and DA₂ dopamine receptor agonists, respectively, since each is devoid of adrenergic effects over an extended dose range. Potential clinical utilities of DA₁ dopamine receptor agonists include the treatment of renal insufficiency and arterial hypertension. DA₂ dopamine receptor agonists may also be useful in treating arterial hypertension, as well as cardiac conditions where facilitation of stroke volume and reduction of myocardial work would be desirable.