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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.

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Nichols DE,Jacob JN,Hoffman AJ,Kohli JD,Glock D

doi

10.1021/jm00378a029

subject

Has Abstract

pub_date

1984-12-01 00:00:00

pages

1701-5

issue

12

eissn

0022-2623

issn

1520-4804

journal_volume

27

pub_type

杂志文章

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