Inhibition of pig kidney L-aromatic amino acid decarboxylase by 2,3-methano-m-tyrosines

Both racemic (E)- and (Z)-2,3-methano-m-tyrosines (9E and 9Z) have been synthesized from a common intermediate, monoester (Z)-1-(ethoxycarbonyl)-2-[3-[(2-methoxyethoxy)methoxy]phenyl] cyclopropanecarboxylic acid (5). Quinine and ephedrine, respectively, were used to resolve their N-tert-butoxycarbon...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1992-04, Vol.35 (8), p.1410-1417
Main Authors: Ahmad, Saeed, Phillips, Robert S, Stammer, Charles H
Format: Article
Language:English
Subjects:
Animals
Aromatic Amino Acid Decarboxylase Inhibitors
Chromatography, High Pressure Liquid
Dopa Decarboxylase - isolation & purification
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Kidney - enzymology
Stereoisomerism
Structure-Activity Relationship
Swine
Tyrosine - analogs & derivatives
Tyrosine - chemical synthesis
Tyrosine - pharmacology
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Summary:Both racemic (E)- and (Z)-2,3-methano-m-tyrosines (9E and 9Z) have been synthesized from a common intermediate, monoester (Z)-1-(ethoxycarbonyl)-2-[3-[(2-methoxyethoxy)methoxy]phenyl] cyclopropanecarboxylic acid (5). Quinine and ephedrine, respectively, were used to resolve their N-tert-butoxycarbonyl (Boc) derivatives. Among the compounds prepared, the (+)-(E)-diastereomer of 9 is the most potent inhibitor of L-aromatic amino acid decarboxylase (Dopa decarboxylase), having a Ki of 22 microM, with the (-)-Z-diastereomer (9Z) second at Ki = 49 microM. (+)-9E is a 45-fold more potent inhibitor of DDC than its acyclic analogue, D-m-tyrosine.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00086a009