Structure of kainic acid totally elucidated by NMR and molecular modelling.
One class of glutamate receptors is characterized by the binding of the neuroexcitant and toxin kainic acid (KA), which contains an embedded L-glutamate moiety in a partially restricted (about the 2,3-bond) conformation. While there are a number of compounds that exhibit high specificity and selectivity at the ionotropic N-methyl-D-aspartate receptor, there has been a lack of selective and high-affinity ligands for the ionotropic KA subclass of excitatory amino acid receptors. This substance has received some attention recently being the least understood of the ionotropic type of glutamate receptor. The spatial orientation of the perceived functional groups of KA has been elucidated by a conformational analysis of an aqueous solution of KA using a combination of nuclear magnetic resonance (NMR) experimental results, mechanics and dynamics calculations, and theoretical simulation of NMR spectra. The weak pH-dependent effects on overall conformation and the structure of the principal '4E-envelope' KA conformer are established in aqueous solution. This study clearly shows the structural 'down' position of the double bond and the preferred 'g(-)-c' conformation of the C(3) carboxymethyl side-chain. The complex structure of this compound is thus definitively resolved. The conformation of the envelope ring such as C(3) carboxymethyl and C(4)-isopropenyl groups may strongly influence the potencies of KA interactions with the KA receptor.
Todeschi
N
N
Université René Descartes-Paris V, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (URA 400 CNRS), France.
Gharbi-Benarous
J
J
Girault
J P
JP
D003198:Computer Simulation; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry*; D018698:Glutamic Acid / Q000737:chemistry; D007608:Kainic Acid / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D007608:Kainic Acid