Asymmetric Synthesis and Receptor Pharmacology of the Group II mGlu Receptor Ligand (1S,2R,3R,5R,6S)-2-Amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid-HYDIA

• Published in: ChemMedChem 2008-02, Vol.3 (2), p.323-335
• Main Authors: Woltering, Thomas J., Adam, Geo, Huguenin, Philipp, Wichmann, Jürgen, Kolczewski, Sabine, Gatti, Silvia, Bourson, Anne, Kew, James N. C., Richards, Grayson, Kemp, John A., Mutel, Vincent, Knoflach, Frédéric
• Format: Article
• Language: English
• Subjects: Alkylation; Animals; asymmetric synthesis; Binding, Competitive; Bridged Bicyclo Compounds - chemical synthesis; Bridged Bicyclo Compounds - pharmacology; dihydroxylation; Excitatory Amino Acid Agonists - chemical synthesis; Excitatory Amino Acid Agonists - pharmacology; Glutamic Acid - chemistry; Glutamic Acid - pharmacology; Hydroxylation; Ligands; LY354740; metabotropic glutamate receptors; mGluR2; Mice; Receptors, Metabotropic Glutamate - agonists; Stereoisomerism; Structure-Activity Relationship
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200700226

The asymmetric synthesis and receptor pharmacology of (1S,2R,3R,5R,6S)‐2‐amino‐3‐Hydroxy‐bicyclo[3.1.0]hexane‐2,6‐dicarboxylic Acid (+)‐9 (HYDIA) and a few of its O‐alkylated derivatives are described. The key step of the synthesis utilizes Sharpless’ asymmetric dihydroxylation (AD‐β) for the kinetic resolution of a bicyclic racemic precursor olefin. In contrast to the bicyclic glutamate analogue LY354740, which is a potent and selective agonist for the group II metabotropic glutamate receptors (mGluRs), these new conformationally restricted and also hydroxylated or alkoxylated glutamate analogues are potent and selective antagonists for the group II mGluRs. Metabotropic glutamate receptor 2/3 ligands: An asymmetric synthesis of (1S,2R,3R,5R,6S)‐2‐amino‐3‐hydroxy‐bicyclo[3.1.0]hexane‐2,6‐dicarboxylic acid (+)‐9 (HYDIA) and a few of its O‐alkylated derivatives is described. These compounds are potent and selective competitive antagonists for the group II mGluRs.