title: Synthesis and biological evaluation of (-)-kainic acid analogues as phospholipase D-coupled metabotropic glutamate receptor ligands.
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 1a-c 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 5a followed by further structural modifications. Only the 4-(1,2,3-triazolyl)-kainate derivative 1c retained the kainate-like agonism, increasing firing in a dose-dependent manner. Further modification of 1c by introduction of a PEG-biotin chain on the 1,2,3-triazole fragment afforded compound 14 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.
authors.affiliation: Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Scotland, UK. m.zanda@abdn.ac.uk.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zanato
authors.forename: Sonia
authors.initials: S
authors.lastname: Watson
authors.forename: Guy S
authors.initials: GS
authors.lastname: Bewick
authors.forename: William T A
authors.initials: WT
authors.lastname: Harrison
authors.forename: Matteo
authors.initials: M
authors.lastname: Zanda
mesh_terms: D000818:Animals; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009470:Muscle Spindles / Q000187:drug effects* / Q000502:physiology; D010739:Phospholipase D / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*
chemical_list: D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; D010739:Phospholipase D; D007608:Kainic Acid