Chemo-enzymatic Synthesis of a Series of 2,4-syn-functionalized (S)-glutamate Analogues: New Insight Into the Structure-Activity Relation of Ionotropic Glutamate Receptor Subtypes 5, 6, and 7

J Med Chem. 2008 Jul 24;51(14):4093-103. doi: 10.1021/jm800092x. Epub 2008 Jun 25.

Abstract

( S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system (CNS) activating the plethora of ionotropic Glu receptors (iGluRs) and metabotropic Glu receptors (mGluRs). In this paper, we present a chemo-enzymatic strategy for the enantioselective synthesis of five new Glu analogues 2a- f ( 2d is exempt) holding a functionalized substituent in the 4-position. Nine Glu analogues 2a- j are characterized pharmacologically at native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), kainic acid (KA), and N-methyl- d-aspartic acid (NMDA) receptors in rat synaptosomes as well as in binding assays at cloned rat iGluR5-7 subtypes. A detailed in silico study address as to why 2h is a high-affinity ligand at iGluR5-7 ( K i = 3.81, 123, 57.3 nM, respectively), while 2e is only a high affinity ligand at iGluR5 ( K i = 42.8 nM). Furthermore, a small series of commercially available iGluR ligands are characterized in iGluR5-7 binding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amination
  • Animals
  • Glutamic Acid / analogs & derivatives*
  • Glutamic Acid / biosynthesis
  • Glutamic Acid / chemical synthesis
  • Glutamic Acid / pharmacology
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Rats
  • Receptors, Glutamate / drug effects*
  • Spectrophotometry, Infrared
  • Structure-Activity Relationship
  • Synaptosomes / drug effects

Substances

  • Receptors, Glutamate
  • Glutamic Acid