Synthesis and biological evaluation of (-)-kainic acid analogues as phospholipase D-coupled metabotropic glutamate receptor ligands

Chiara Zanato*, Sonia Watson, Guy S. Bewick, William T A Harrison, Matteo Zanda

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

(-)-Kainic acid potently increases stretch-induced afferent firing in muscle spindles, probably acting through a hitherto uncloned phospholipase D (PLD)-coupled mGlu receptor. Structural modification of (-)-kainic acid was undertaken to explore the C-4 substituent effect on the pharmacology related to muscle spindle firing. Three analogues were synthesised by highly stereoselective additions of a CF3, a hydride and an alkynyl group to the Re face of the key pyrrolidin-4-one intermediate followed by further structural modifications. Only the 4-(1,2,3-triazolyl)-kainate derivative retained the kainate-like agonism, increasing firing in a dose-dependent manner. Further modification of by introduction of a PEG-biotin chain on the 1,2,3-triazole fragment afforded compound which retained robust agonism at 1 μM and appears to be suitable for future use in pull-down assays and far western blotting for PLD-mGluR isolation.

Original languageEnglish
Pages (from-to)9638-9643
Number of pages6
JournalOrganic & Biomolecular Chemistry
Volume12
Issue number47
Early online date14 Oct 2014
DOIs
Publication statusPublished - 21 Dec 2014

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