title: Conformational analysis of glutamic acid analogues as probes of glutamate receptors using molecular modelling and NMR methods. Comparison with specific agonists.
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.
authors.affiliation: Université René Descartes-Paris V, Laboratoire de Chimie et BiochimiePharmacologique et Toxicologique, (URA 400 CNRS), Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Todeschi
authors.forename: J
authors.initials: J
authors.lastname: Gharbi-Benarous
authors.forename: F
authors.initials: F
authors.lastname: Acher
authors.forename: V
authors.initials: V
authors.lastname: Larue
authors.forename: J P
authors.initials: JP
authors.lastname: Pin
authors.forename: J
authors.initials: J
authors.lastname: Bockaert
authors.forename: R
authors.initials: R
authors.lastname: Azerad
authors.forename: J P
authors.initials: JP
authors.lastname: Girault
mesh_terms: D000818:Animals; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000494:pharmacology*; D018698:Glutamic Acid / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015335:Molecular Probes; D018092:Kainic Acid Receptors / Q000819:agonists; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000737:chemistry*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D014981:Xenopus
chemical_list: D003515:Cycloleucine; D018690:Excitatory Amino Acid Agonists; D018698:Glutamic Acid; D015335:Molecular Probes; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C036361:1-amino-1,3-dicarboxycyclopentane