First enantiospecific synthesis of a 3,4-dihydroxy-L-glutamic acid [(3S,4S)-DHGA], a new mGluR1 agonist

Bioorg Med Chem Lett. 2000 Jan 17;10(2):129-33. doi: 10.1016/s0960-894x(99)00641-1.

Abstract

The first synthesis of one of the 4 possible stereoisomers of 3,4-dihydroxy-L-glutamic acid ((3S,4S)-DHGA 3), a natural product of unknown configuration, is described. The synthesis is based on the Lewis acid catalyzed reaction of benzyl alcohol with a D-ribose-derived 2,3-aziridino-gamma-lactone 4-benzyl carboxylate (6). Preliminary pharmacological studies showed that (3S,4S)-3 is an agonist of metabotropic glutamate receptors of type 1 (mGluR1) and a weak antagonist of mGluR4 but has no discernible activity with respect to mGluR2. This activity profile can be rationalized by fitting extended conformations of (3S,4S)-3 in proposed models of each of these receptor subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Glutamates / chemical synthesis*
  • Glutamates / pharmacology
  • Glutamic Acid / analogs & derivatives*
  • Glutamic Acid / chemical synthesis
  • Glutamic Acid / pharmacology
  • Humans
  • Inositol Phosphates / analysis
  • Models, Molecular
  • Molecular Conformation
  • Receptors, Metabotropic Glutamate / agonists*
  • Stereoisomerism
  • Type C Phospholipases / metabolism

Substances

  • 3,4-dihydroxyglutamic acid
  • Glutamates
  • Inositol Phosphates
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • Glutamic Acid
  • Type C Phospholipases