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 α-(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+-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, χ1 [α-CO2––C(2)–C(3)–C(4)] and χ2 [+NC(2)–C(3)–C(4)–γ-CO2–] and by the two characteristic distances between the potentially active functional groups, α-N+–γ-CO2– (d1) and α-CO2––γ-CO2– (d2). 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.