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.

doi:10.1021/JM00378A029

Paper

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 Dec 1, 1984 · D. Nichols, J. N. Jacob, A. J. Hoffman

Journal of medicinal chemistry

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5

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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.

Study Snapshot

2-Methylation of 6-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN) abolishes its DA1 dopamine agonist activity, likely due to steric effects of the 2-methyl group on the dopamine

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

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.

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References

Citations

A stereochemical and conformational model of dopaminergic agonist and antagonist activity: further evaluation.

The optimal conformer for dopaminergic activity is relatively low energy, explaining the relative activity of compounds and predicting potent antagonists and antagonism.

Dopamine and Dopaminergic Ligands

Dopamine receptors show stereoselectivity towards chiral dopaminergic ligands, similar to acetylcholine and histamine, and share similarities with adrenergic agents.

Dopamine agonists: structure-activity relationships.

Dopamine agonists show structure-activity correlations and metabolism aspects, which influence drug design strategies and structure-activity considerations.