C(2)-Methylation abolishes DA1 dopamine agonist activity of 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN): steric intolerance by the receptor

• Published in: Journal of medicinal chemistry Vol. 27; no. 12; pp. 1701 - 1705
• Main Authors: Nichols, David E, Jacob, James N, Hoffman, Andrew J, Kohli, Jai D, Glock, Dana
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.12.1984
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Animals; Chemistry; Dogs; Dopamine - analogs & derivatives; Dopamine - pharmacology; Exact sciences and technology; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Molecular Conformation; Naphthalenes - chemical synthesis; Naphthalenes - pharmacology; Organic chemistry; Preparations and properties; Receptors, Dopamine - drug effects; Receptors, Dopamine - metabolism; Renal Artery - drug effects; Renal Artery - physiology; Spectrophotometry, Infrared; Tetrahydronaphthalenes - chemical synthesis; Tetrahydronaphthalenes - pharmacology; Vasodilation - drug effects; Vasodilator Agents - chemical synthesis; Condensation reaction; Cyclization; Structure activity relation; Dopamine agonist; Bicyclic compound; Benzenic compound; Methylation; NMR spectrum; Ketone; Diphenols
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00378a029

The synthesis of 2-amino-2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene is reported. This compound did not produce vasodilation in the dog renal artery and was inactive as a DA1-type dopamine agonist. This is in contrast to the 2-nonmethylated homologue 6,7-ADTN, which is a potent DA1 agonist. High-field 1H NMR studies of the O,O-dimethyl ethers for both compounds as their free bases in chloroform-d revealed that the 2-methyl homologue probably exists as a rapidly equilibrating mixture of conformers; it seems likely that it can adopt the active conformation proposed to be required by the dopamine receptor. The lack of activity is therefore attributed to the steric effect of the 2-methyl group, consistent with explanations offered by others that the dopamine receptor cannot tolerate alkylation at the alpha side-chain carbon.