Improved synthesis and in vitro/in vivo activities of natural product-inspired, artificial glutamate analogs

Masato Oikawa*, Minoru Ikoma, Makoto Sasaki, Martin B. Gill, Geoffrey T. Swanson, Keiko Shimamoto, Ryuichi Sakai

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Here, we report our second-generation synthesis of 12 artificial glutamate analogs, starting from heterotricycle intermediates 3a-3d, readily prepared in three steps including tandem Ugi/Diels-Alder reactions. The new synthesis employs imidate intermediates for the deoxygenation of pyrrolidones (10a-10d to 6a-6d), and each advanced intermediate 6a-6d was diversified into three glutamate analogs (1a-1d, 5a-5d, 7a-7d) in 1-2 steps. In vitro electrophysiological assays revealed that the new piperidine-type analog 7c alters neuronal function with lower potency than 1a. Conversely, intracranial injection of 7c into mice produced a greater degree of hypoactivity than 1a. Our recent investigation has revealed that this series of compounds antagonizes AMPA-type glutamate receptor-mediated currents in a subtype selective manner. The more efficient syntheses of this novel set of neuroactive molecules will facilitate their pharmacological characterization.

Original languageEnglish (US)
Pages (from-to)3795-3804
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number11
DOIs
StatePublished - Jun 1 2010

Keywords

  • Deoxygenation of amide
  • Diversity-oriented synthesis
  • Glutamate receptor
  • Hypoactivity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Improved synthesis and in vitro/in vivo activities of natural product-inspired, artificial glutamate analogs'. Together they form a unique fingerprint.

Cite this