Neuroinhibitory effects of SK&F 85174, a novel dopamine receptor agonist

SK&F 85174 (3-allyl-6-chloro-2,3,4,5-tetra-hydro-1-(4-hydroxy-phenyl)-1-H-3-benzaze pine-7, 8-diol methanesulfonate) the N-allyl derivative of SK&F 82526, a selective postjunctional dopaminergic agonist, retains the potent agonist activity of the parent molecule at the postjunctional dopamine receptor, as evidenced by activation of the dopamine-sensitive adenylate cyclase in rat caudate homogenates (EC50 = 11 nM). However, unlike SK&F 82526, SK&F 85174 is a potent inhibitor of adrenergic neurotransmission. This neuroinhibitory effect can be demonstrated both in isolated vascular preparations, and in in situ preparations in the anesthetized dog measuring both cardiac and vascular neurotransmission. In each of these preparations, the effect of SK&F 85174 can be blocked by the dopamine receptor antagonists, metoclopramide, or 1-sulpiride, showing that its action occurs via activation of prejunctional dopamine receptors. Inhibition of the responses to sympathetic nervous system activation, when combined with the ability to increase renal blood flow by stimulation of postjunctional dopamine receptors, could make SK&F 85174 an effective therapeutic agent for a variety of cardiovascular disorders, including angina pectoris, hypertension, and congestive heart failure.