Conformational analysis of glutamic acid analogues as probes of glutamate receptors using molecular modelling and NMR methods. Comparison with specific agonists

Bioorg Med Chem. 1997 Feb;5(2):335-52. doi: 10.1016/s0968-0896(96)00252-0.

Abstract

The activity of five glutamic acid analogues substituted in position 3 or 4 by a methyl (3T, 3E, 4T, and 4E) or a methylene group (4M) has been examined at one cloned Glu receptor subtype, mGluR1. These analogues interact with glutamate receptors of the central nervous system, especially the ligand 4T [(2S,4S)-4-methylglutamic acid] at the metabotropic glutamate receptor mGluR1. It was observed that only the 4T isomer is as potent an agonist as glutamic acid, whereas other isomers are less active. Furthermore, 4E [(2S,4R)-4-methylglutamic acid] exhibited an exceptional selectivity for the KA ionotropic receptor subtype while 4M [(2S)-4-methyleneglutamic acid] was active at the NMDA receptors. These molecules represent suitable tools among a population of similar glutamate analogues for a classical structure-function relationship study. We have undertaken a conformational analysis by 1H and 13C NMR spectroscopy and molecular modelling of these molecules. Hetero- and homonuclear coupling constants were measured in order to assign the diastereotopic methylene protons at C(3) or C(4), and used for comparison in molecular dynamics (MD) simulations. The hydrogen-bonding possibility, steric effects or electrostatic interactions may be a considerable influence in stabilizing a conformational population in D2O solution. The conformations may be grouped by the two backbone torsion angles, chi 1 [alpha-CO2(-)-C(2)-C(3)-C(4)] and chi 2 [+NC(2)-C(3)-C(4)-gamma CO2-] and by the two characteristic distances between the potentially active functional groups, alpha N(+)-gamma CO2- (d1) and alpha CO2(-)-gamma CO2- (d2). The conformational preferences in solution of 4T, 4E and (3T, 3E, 4M) are discussed in the light of the physical features known for a specific metabotropic agonist (ACPD) and specific ionotropic agonists (KA) and (NMDA), respectively.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cycloleucine / analogs & derivatives
  • Cycloleucine / chemistry
  • Cycloleucine / pharmacology
  • Excitatory Amino Acid Agonists / chemistry
  • Excitatory Amino Acid Agonists / pharmacology*
  • Glutamic Acid / chemistry*
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Molecular Probes
  • Receptors, Kainic Acid / agonists
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / chemistry*
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Xenopus

Substances

  • Excitatory Amino Acid Agonists
  • Molecular Probes
  • Receptors, Kainic Acid
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • Cycloleucine
  • 1-amino-1,3-dicarboxycyclopentane
  • Glutamic Acid