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 language | English |
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Pages (from-to) | 9638-9643 |
Number of pages | 6 |
Journal | Organic & Biomolecular Chemistry |
Volume | 12 |
Issue number | 47 |
Early online date | 14 Oct 2014 |
DOIs | |
Publication status | Published - 21 Dec 2014 |
Bibliographical note
SW was supported by a SULSA Bioskape/Eli Lilly studentship.Fingerprint
Dive into the research topics of 'Synthesis and biological evaluation of (-)-kainic acid analogues as phospholipase D-coupled metabotropic glutamate receptor ligands'. Together they form a unique fingerprint.Profiles
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Guy Bewick
- School of Medicine, Medical Sciences & Nutrition, Neuroscience
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Cardiovascular and Diabetes Centre
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Senior Lecturer
- School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences
Person: Academic