Conformational analysis of 2-(carboxycyclopropyl)glycine agonists of glutamate receptors in aqueous solution using a combination of NMR and molecular modelling experiments and charge calculations

Abstract

Two classes of glutamate receptors [metabotropic (group-II) and ionotropic (NMDA) subclasses] are characterized by the binding of -(carboxycyclopropyl)glycine (CCG) isomers, (2S,3S,4S)-CCG (L-CCG-I) and (2S,3R,4S)-CCG (L-CCG-IV) which contain an embedded L-glutamate moiety in a partially restricted conformation [relative to the C(3)᎐C(4) bond]. The spatial orientation of the perceived functional groups have been elucidated by a conformational analysis in aqueous solution of L-CCG-I and L-CCG-IV using a combination of NMR experimental results, theoretical simulation of NMR spectra, mechanics and dynamics calculations. It was of interest to compare the charge distributions resulting from a number of quantum calculations on the cyclopropane ring. One important conclusion of the study is that the best theoretical model is the MD in solvent. This study shows clearly the preferred 't-A' and 'g ϩ -B' conformations of the C(3) aminocarboxymethyl side chain for L-CCG-I and L-CCG-IV, respectively. Weak pH-dependent effects on the structure of the principal L-CCG-I and L-CCG-IV conformers have been established in aqueous solution. The conformations may be grouped by the two backbone torsion angles, 1 [ -CO 2 ؊ ᎐C(2)᎐C(3)᎐C(4)] and 2 [ ϩ NC(2)᎐C(3)᎐C(4)᎐ -CO 2 ؊ ] and by the two characteristic distances between the potentially active functional groups, -N ϩ --CO 2 ؊ (d 1 ) and -CO 2 ؊ --CO 2 ؊ (d 2 ). The conformational preferences in solution of L-CCG-I and L-CCG-IV are discussed in the light of the physical features known for specific metabotropic (ACPD) and specific ionotropic (NMDA) agonists, respectively.

Subtype selective kainic acid receptor agonists: Discovery and approaches to rational design

“…2). 38 Early on, it was hypothesized that the Glu agonist binding mode(s) to the Glu receptors, was-or were-likely found among these nine local energy minima. This is because binding of Glu in an eclipsed conformation would automatically induce an energy penalty, resulting in lower binding affinity.…”

Stereoselective Synthesis of l-2-(Carboxycyclopropyl)glycines via Stereocontrolled 1,3-Dipolar Cycloadditions of Diazomethane on Z- and E-3,4-l-Didehydroglutamates OBO Esters

“…Several structural analogues of l -glutamic acid have been synthesized and found to be more specific agonists than l -Glu which not only activates mGluRs but also the ionotropic glutamate receptors. − Some conformationally constrained analogues of l -Glu recognize and bind to the various types of glutamate receptors in exclusive or preferential manner. Among them, the 2,3- and 3,4-methano derivatives of l -Glu are most prominent; the latter compounds are also referred to as carboxycyclopropylglycines (CCGs). The four isomeric CCG-I − CCG-IV were found to be agonists for either the N -methyl- d -aspartic acid (NMDA) or the metabotropic l -glutamate receptor .…”

4,4‐Dimethyl‐ and Diastereomeric 4‐Hydroxy‐4‐methyl‐ (2S)‐Glutamate Analogues Display Distinct Pharmacological Profiles at Ionotropic Glutamate Receptors and Excitatory Amino Acid Transporters

“…Glu is a highly flexible molecule which may adopt nine staggered conformations 42. Among these, it is well documented that Glu binds in a folded conformation to the iGluRs,28, 43 and in an extended conformation to the mGluRs44 (Figure 2).…”