Studies toward creation of chemical probes for dissecting structural dynamics of ionotropic glutamate receptors

2014 Fiscal Year Final Research Report

• Project/Area Number: 25560418
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Chemical biology
• Research Institution: Yokohama City University
• Principal Investigator: OIKAWA Masato 横浜市立大学, 生命ナノシステム科学研究科, 教授 (70273571)
• Co-Investigator(Kenkyū-buntansha): SAKAI Ryuichi 北海道大学, 大学院水産科学研究科, 教授 (20265721)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 化学プローブ / イオンチャネル型グルタミン酸受容体 / 人工リガンド

Outline of Final Research Achievements

Chemical probes are important tools to elucidate functions of target proteins. Development of chemical probes for ionotropic glutamate receptor (iGluRs), that mediates majority of fast excitatory neurotransmission in the central nervous system (CNS), is highly challenging due to the unique structure of the ligand binding domain. Dysiherbaine (DH), which was isolated from Micronesian marine sponge Lendenfeldia chondrodes in 1997 by Sakai et al, is a potent agonist selective to GluK1- and GluK2-containing subtypes of kainate type iGluR. In the present study, we planned to synthesize clickable DH as a precursor for the chemical probe.
We first synthesized the vital intermediate, which has three stereocenters, performed in 10 steps starting from D-ribose. The key transformation includes domino aldol-Cannizzaro reaction followed by stereoselective aldol reaction at the ring juncture of the bicyclo[3.3.0]octane skeleton, and stereoselective addition of vinyl group to the lactol moiety.

Free Research Field

有機合成化学、ケミカルバイオロジー