Predictive study by molecular modeling to promote specific probes of glutamate receptors, using methylated cyclic glutamic acid derivatives (trans- and cis-ACPD). Comparison with specific agonists.
Two classes of glutamate receptors (metabotropic and ionotropic) and their subclasses (groups I-III and N-methyl-D-aspartic acid (NMDA), kainic acid (KA)), respectively, are characterized by the binding of a L-glutamate moiety in a specific conformation. The conformations may be grouped by the two backbone torsion angles, chi1 [alpha-CO2-C(2)-C(3)-C4)] and chi2 [+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 of 2,3,4-methyl(a and b)-cis and trans-1-aminocyclopentane-1,3-dicarboxylate are discussed in the light of the physical features known for specific metabotropic (groups I-II) and specific ionotropic (NMDA, KA) agonists, respectively. The spatial orientation of the perceived functional groups was elucidated in cyclic derivatives which contain an embedded L-glutamate moiety in a particularly restricted conformation (relative to the C(2)-C(3)-C(4) bond) using a combination of NMR experimental results and mechanics and dynamics calculations. One important conclusion of the study is that a single glutamate receptor is privileged for each theoretical model considered by molecular dynamics. This study showed clearly what would be conformational preferences of cyclic glutamate derivatives following the geometrical isomerism of the methyl group.
Université René Descartes-Paris, France.
N
N
Evrard-Todeschi
J
J
Gharbi-Benarous
V
V
Larue
J P
JP
Girault
D003198:Computer Simulation; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D008958:Models, Molecular; D008968:Molecular Conformation; D015335:Molecular Probes / Q000737:chemistry; D017470:Receptors, Glutamate / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D018690:Excitatory Amino Acid Agonists; D015335:Molecular Probes; D017470:Receptors, Glutamate; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane