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

ChemMedChem. 2008 Feb;3(2):323-35. doi: 10.1002/cmdc.200700226.

Abstract

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-beta) 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.

MeSH terms

  • Alkylation
  • Animals
  • Binding, Competitive
  • Bridged Bicyclo Compounds / chemical synthesis
  • Bridged Bicyclo Compounds / pharmacology*
  • Excitatory Amino Acid Agonists / chemical synthesis
  • Excitatory Amino Acid Agonists / pharmacology*
  • Glutamic Acid / chemistry
  • Glutamic Acid / pharmacology
  • Hydroxylation
  • Ligands
  • Mice
  • Receptors, Metabotropic Glutamate / agonists*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 2-amino-3-hydroxybicyclo(3.1.0)hexane-2,6-dicarboxylic acid
  • Bridged Bicyclo Compounds
  • Excitatory Amino Acid Agonists
  • Ligands
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • Glutamic Acid
  • eglumetad