Based on our preliminary finding that beta-phenyl dopamine possesses a dopamine-like vasodilatory action in the canine renal artery, we propose to systematically evaluate a series of beta-substituted dopamine congeners. Obvious similarities between such analogues and some recently-reported, highly site-selective 1-phenyl-3-benzazepine dopamine agonists indicate that a study of beta-substituted dopamine type molecules may lead to some long-sought answers about the differences between dopamine receptor subtypes. It is further proposed to examine several rigid and conformationally restricted beta-alkyl dopamine type congeners, in order to delineate the binding requirements of the different receptor subtypes. In addition to this work, we will also examine the possibility that differences in the acidity of the phenolic hydroxy group may influence receptor selectivity. This will be accomplished by an examination of several mono-hydroxy-mono-halogenated dopamine congeners. pKa will be used as a measure of acidity and determinations will be made for all compounds. Biological assay will be made in vivo in dog renal artery and femoral artery preparations. Vasodilation of the renal artery will be taken as a measure of DA1 type agonist activity and dilation of the femoral artery will be used as a measure of DA2 type agonist activity. These assays will be most appropriate for evaluation of the synthesized compounds for possible use in treatment of shock or for use in novel approaches to control of hypertension. We will attempt the resolution and determination of absolute configuration for any racemate which shows relatively high dopaminergic potency or for any racemate which shows high selectivity for a particular receptor type.
