Conformational requirements for norepinephrine uptake inhibition by phenethylamines in brain synaptosomes. Effects of alpha-alkyl substitution.

de Jong AP, Fesik SW, Makriyannis A
J Med Chem. 1982 25 (12): 1438-41

PMID: 7154004 · DOI:10.1021/jm00354a009

Amphetamine is a strong competitive antagonist of brain synaptosomal [3H]norepinephrine ([3H]NE) uptake. Its alpha-ethyl analogue is much less active, while 2-aminotetralin and 1,2-dihydro-2-aminonaphthalene, in which the alpha-ethyl group is tied to the aromatic ring, possess about the same inhibitory potency as amphetamine. The conformational properties of these compounds in solution were studied by 1H and 13C NMR methods. Only small differences between amphetamine and alpha-ethylphenethylamine hydrochlorides were observed in the relative rotamer populations due to rotation around the C alpha -C beta bond of the side chain. In D2O the gauche conformation is slightly favored, while in CDCl3 the trans conformation is the predominant one. Conformational analysis of the alpha-ethyl group in alpha-ethylphenethylamine showed that this group exists in two equally populated conformations in both solvents. It is suggested that these conformations hinder the approach of alpha-ethylphenethylamine to the brain synaptosomal NE uptake sites.

MeSH Terms (14)

Alkylation Amphetamine Animals Brain In Vitro Techniques Male Molecular Conformation Naphthalenes Norepinephrine Phenethylamines Rats Rats, Inbred Strains Synaptosomes Tetrahydronaphthalenes

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