7 グルタミン酸受容体の立体配座要請 : 配座制御アミノ酸合成によるアプローチ(口頭発表の部)

抄録

Glutamate receptors mediate synaptic excitation in the mammalian central nervous system. The receptors have been classified into two major classes, ionotropic glutamate receptors and metabotropic glutamate receptors. Our recent work concerning the syntheses and the pharmacology of L-2-(carboxycyclopropyl)-glycines (L-CCG-1〜IV) have demonstrated that an extended conformer of L-glutamate is one of the most effective factor for activating metabotropic glutamate receptors, and a folded one for NMDA receptors. In this study, conformational requirements of glutamate receptors regarding rotamers around α-amino acid moiety have been examined by the spectroscopic studies of CCGs and by the synthesis of the 3'-substituted analogues of CCGs, L-2-(2-carboxy-3-methoxymethylcyclopropyl)glycines (cis- and trans-MCGs), which freeze CCG's possible rotamers at C2-C1'. NMR studies of CCGs under variable pHs and variable temperatures indicated that the C2-C1' bond of CCGs can not freely rotate but relatively fixes either CC or NC conformer in aqueous solution (Figure 2). This was well supported by the facts that the conformationally frozen analogues of CCGs [cis-MCG-I (NC conformer) and IV (CC conformer), Figure 4,5], synthesized from D-serinal derivative in a stereocontrolled manner, showed similar activities as that of L-CCG-I and IV, respectively. Thus, we propose that the conformational requirement of metabotropic glutamate receptors is an anti-(NC) conformer of L-glutamate and that of NMDA receptors is a gauche-(CC), as shown in Figure 6. In addition, trans-MCG-IV and CPG-IV exhibited kainate-type responses at the dorsal root C-fibre of the immature rat. These results suggest that a folded form of L-glutamate, gauche-(CC), is also responsible for activating kainate receptors.