Rational Design, Synthesis, and Pharmacological Evaluation of 2-Azanorbornane-3-exo,5-endo-dicarboxylic Acid:  A Novel Conformationally Restricted Glutamic Acid Analogue

The design and synthesis of conformationally restricted analogues of α-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) (IC50 > 300 μM, [3H]AMPA) or kainic acid (IC50 > 160 μM, [3H]kainic acid) receptors nor in binding studies on the cloned iGluR5,6 subtypes (IC50 > 300 μM, [3H]kainic acid).