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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

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Graduate School of Nanobioscience, Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, Illinois 60611, United States
§ Faculty of Fisheries Sciences, Hokkaido University, Hakodate 041-8611, Japan
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark
*Phone: +81-45-787-2403. Fax: +81-45-787-2403. E-mail: [email protected]
Cite this: J. Med. Chem. 2013, 56, 6, 2283–2293
Publication Date (Web):February 23, 2013
https://doi.org/10.1021/jm301590z
Copyright © 2013 American Chemical Society

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    Abstract

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    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.

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    Synthetic procedure, characterization, and 1H and 13C NMR spectra of new compounds; single-crystal X-ray diffraction experiment of 8 (2R); behavioral effects of (2R)- and (2S)-IKM-159 on mice. This material is available free of charge via the Internet at http://pubs.acs.org.

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