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

• Oikawa, Masato

• Ikoma, Minoru

• Sasaki, Makoto

• Gill, Martin B.

• Swanson, Geoffrey T.

• Shimamoto, Keiko

• Sakai, Ryuichi

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.

Journal

• Bioorganic & Medicinal Chemistry

  Bioorganic & Medicinal Chemistry 18 (11), 3795-3804, 2010-06-01

  Elsevier

Keywords

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

Details

• CRID: 1050845763935993344
• NII Article ID: 120002169301
• HANDLE: 2115/43115
• ISSN: 09680896
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • CiNii Articles