Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: Asymmetric synthesis, neuroactivity, and structural characterization

Lina Juknaitě, Yutaro Sugamata, Kazuya Tokiwa, Yuichi Ishikawa, Satoshi Takamizawa, Andrew Eng, Ryuichi Sakai, Darryl S. Pickering, Karla Frydenvang, Geoffrey T. Swanson, Jette S. Kastrup, Masato Oikawa*

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4- methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors.

Original languageEnglish (US)
Pages (from-to)2283-2293
Number of pages11
JournalJournal of Medicinal Chemistry
Volume56
Issue number6
DOIs
StatePublished - Mar 28 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Juknaitě, L., Sugamata, Y., Tokiwa, K., Ishikawa, Y., Takamizawa, S., Eng, A., Sakai, R., Pickering, D. S., Frydenvang, K., Swanson, G. T., Kastrup, J. S., & Oikawa, M. (2013). Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: Asymmetric synthesis, neuroactivity, and structural characterization. Journal of Medicinal Chemistry, 56(6), 2283-2293. https://doi.org/10.1021/jm301590z