Specific dopamine D-1 and DA1 properties of 4-(mono- and -dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline and its tetrahydrothieno[2,3c]pyridine analog

• Published in: Journal of medicinal chemistry Vol. 30; no. 8; pp. 1454 - 1458
• Main Authors: Riggs, Robert M, Nichols, David E, Foreman, Mark M, Truex, Lewis L, Glock, Dana, Kohli, Jai D
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.08.1987
• Subjects: Adenylyl Cyclases - metabolism; Animals; Chemical Phenomena; Chemistry; Dogs; Dopamine - pharmacology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Isoquinolines - pharmacology; Male; Organic chemistry; Preparations and properties; Pyridines - pharmacology; Rats; Receptors, Dopamine - drug effects; Receptors, Dopamine - physiology; Receptors, Dopamine D1; Receptors, Dopamine D2; Renal Artery - physiology; Retina - enzymology; Structure-Activity Relationship; Thiophenes - pharmacology; Vasodilation - drug effects; Sulfur nitrogen heterocycle; Agonist; Nitrogen heterocycle; Bicyclic compound; Phenols; Antidepressant agent; Benzenic compound; Aromatic compound; Diphenols; Biological activity; Dopaminergic receptor D1
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00391a029

The title compounds were prepared and examined to elucidate further the structure-activity relationships of dopamine agonists related to nomifensine. Two of the compounds, 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline and 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydrothieno[2,3-c]pyridine, have been reported in the patent literature. In stimulation of rat retinal adenylate cyclase, a measure of dopamine D-1 agonist activity, the tetrahydroisoquinoline was about equipotent to dopamine. The thienyl isostere had nearly twice the potency. Both compounds were potent vasodilators in the canine renal artery, producing dilation through stimulation of DA1 type peripheral dopamine receptors. A monohydroxy analogue, 4-(3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline, had only slight activity in the cyclase assay and was inactive in the canine renal artery. These results, combined with those from an earlier study, demonstrate that N-alkylation decreases both dopamine D-1 and DA-1 agonist potency, with activity ordered as H greater than methyl greater than ethyl greater than propyl. The results also demonstrate the necessity for the catechol function in this series.