Synthesis and biological evaluation of (-)-kainic acid analogues as phospholipase D-coupled metabotropic glutamate receptor ligands.
Org Biomol Chem
; 12(47): 9638-43, 2014 Dec 21.
Article
en En
| MEDLINE
| ID: mdl-25347058
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fosfolipasa D
/
Husos Musculares
/
Receptores de Glutamato Metabotrópico
/
Ácido Kaínico
Límite:
Animals
Idioma:
En
Año:
2014
Tipo del documento:
Article