Rational Design, Synthesis, and Pharmacological Evaluation of 2-Azanorbornane-3-<i>exo</i>,5-<i>endo</i>-dicarboxylic Acid: A Novel Conformationally Restricted Glutamic Acid Analogue
2003-01-16T00:00:00Z (GMT) by
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-<i>exo</i>,5-<i>endo</i>-dicarboxylic acid (<b>1</b>), a novel conformationally restricted (<i>S</i>)-glutamic acid (Glu) analogue intended as a mimic of the <i>folded Glu conformation</i>. The synthesis of <b>1</b> 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 (±)-<b>1</b> did not show affinity in binding studies on native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) (IC<sub>50</sub> > 300 μM, [<sup>3</sup>H]AMPA) or kainic acid (IC<sub>50</sub> > 160 μM, [<sup>3</sup>H]kainic acid) receptors nor in binding studies on the cloned iGluR5,6 subtypes (IC<sub>50</sub> > 300 μM, [<sup>3</sup>H]kainic acid).