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.
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.
D000818:Animals; D004285:Dogs; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008968:Molecular Conformation; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D013055:Spectrophotometry, Infrared; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000138:chemical synthesis*
D007202:Indicators and Reagents; D009281:Naphthalenes; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; D014665:Vasodilator Agents; C011639:ADTN; C043915:2-amino-2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene; D004298:Dopamine