Rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid: a novel conformationally restricted glutamic acid analogue

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The design and synthesis of conformationally restricted analogues of alpha-amino acids is an often used strategy in medicinal chemistry research. Here we present the rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid (1), a novel conformationally restricted (S)-glutamic acid (Glu) analogue intended as a mimic of the folded Glu conformation. The synthesis of 1 was completed in its racemic form in eight steps from commercially available starting materials. As a key step, the first facially selective hydroboration of a 5-methylidene[2.2.1]bicyclic intermediate was investigated. In this transformation, the catalytic methodology of Wilkinson's/catechol borane proved superior to stoichiometric borane or dialkyl borane reagents, in terms of higher diastereomeric excess and chemical yield. To our surprise (+/-)-1 did not show affinity in binding studies on native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) (IC(50) > 300 microM, [(3)H]AMPA) or kainic acid (IC(50) > 160 microM, [(3)H]kainic acid) receptors nor in binding studies on the cloned iGluR5,6 subtypes (IC(50) > 300 microM, [(3)H]kainic acid).
Original languageEnglish
JournalJournal of Organic Chemistry
Issue number4
Pages (from-to)1489-95
Number of pages7
Publication statusPublished - 2003

    Research areas

  • Aza Compounds, Dicarboxylic Acids, Glutamic Acid, Inhibitory Concentration 50, Kainic Acid, Magnetic Resonance Spectroscopy, Molecular Conformation, Molecular Mimicry, Molecular Structure, Norbornanes, Receptors, Glutamate, Stereoisomerism, Structure-Activity Relationship, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

ID: 40371578