STUDIES DIRECTED TOWARD THE DESIGN OF SPECIFIC DOPAMINE D-1/DA-1 AGONISTS AND ANTAGONISTS
Abstract
The central dopamine D-1 receptor is positively coupled to adenylate cyclase. However, the biology of this receptor is still largely unknown. The vascular dopamine DA(,1) receptor is also positively coupled to adenylate cyclase. It is responsible for dilation of several vascular beds. The phenylbenzazepine SKF 38393 and the 4-phenyl-1,2,3,4-tetrahydroisoquinoline, 3',4'-dihydroxynomifensine, were the first selective D-1/DA(,1) agonists. The phenylbenzazepine SCH 23390 was the first selective D-1/DA(,1) antagonist. To further explore the requirements for selective D-1/DA(,1) agonists and antagonists, three classes of compounds were synthesized and evaluated: simple beta-alkyl derivatives of dopamine; 4-phenyl-1,2,3,4-tetrahydroisoquinolines as analogs of 3'-4'-dihydroxynomifensine and SCH 23390; and several cis-hexahydrobenzo a phenanthridines as rigid analogs of 3'-4'-dihydroxynomifensine. From the beta-alkyl dopamine data, it was concluded that 2- (3,4-dihydroxyphenyl)-2-phenethylamine is the dopamine D-1/DA(,1) agonist "pharmacophore". From the 4-phenyl-1,2,3,4-tetrahydro- isoquinoline data, a catechol moiety and a secondary amine group are required for optimum dopamine D-1/DA(,1) activity. The tetra- hydrothieno 2,3c -pyridine analog was the most potent agonist of all compounds tested. For dopamine D-1 antagonist activity, the required "pharmacophore" is N-methyl-2-(3-hydroxyphenyl)-2-phenethylamine. The 10,11-dihydroxy-5,6,6a,7,8,12b-hexahydro- benzo a phenanthridine and the hexahydrothieno a phenanthridine analog had reduced dopamine D-1 agonist properties in comparison to 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline. Antagonist properties of the 11-hydroxy analog and its N-methyl derivative were comparable to the antagonist properties of the 4-phenyl-1,2,3,4-tetrahydroisoquinolines. There was preliminary evidence presented to indicate that the dopamine D-1 receptor lacks a rotameric preference for the binding of 4-phenyl-1,2,3,4-tetrahydroisoquinolines. Other preliminary evidence suggested a subtle dissimilarity exists between the central dopamine D-1 receptor and the vascular dopamine DA(,1) receptor.
Degree
Ph.D.
Subject Area
Pharmacology
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