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

Fingerprint

Phospholipase D
glutamates
Metabotropic Glutamate Receptors
Kainic Acid
spindles
analogs
Ligands
muscles
Muscle Spindles
ligands
acids
evaluation
synthesis
pharmacology
Muscle
biotin
Far-Western Blotting
hydrides
Triazoles
isolation

Cite this

Synthesis and biological evaluation of (-)-kainic acid analogues as phospholipase D-coupled metabotropic glutamate receptor ligands. / Zanato, Chiara; Watson, Sonia; Bewick, Guy S.; Harrison, William T A; Zanda, Matteo.

In: Organic & Biomolecular Chemistry, Vol. 12, No. 47, 21.12.2014, p. 9638-9643.

Research output: Contribution to journalArticle

@article{cbc1d8e41d564fe5b08a0eb81eff9323,
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 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.",
author = "Chiara Zanato and Sonia Watson and Bewick, {Guy S.} and Harrison, {William T A} and Matteo Zanda",
note = "SW was supported by a SULSA Bioskape/Eli Lilly studentship.",
year = "2014",
month = "12",
day = "21",
doi = "10.1039/c4ob02002b",
language = "English",
volume = "12",
pages = "9638--9643",
journal = "Organic & Biomolecular Chemistry",
issn = "1477-0520",
publisher = "The Royal Society of Chemistry",
number = "47",

}

TY - JOUR

T1 - Synthesis and biological evaluation of (-)-kainic acid analogues as phospholipase D-coupled metabotropic glutamate receptor ligands

AU - Zanato, Chiara

AU - Watson, Sonia

AU - Bewick, Guy S.

AU - Harrison, William T A

AU - Zanda, Matteo

N1 - SW was supported by a SULSA Bioskape/Eli Lilly studentship.

PY - 2014/12/21

Y1 - 2014/12/21

N2 - (-)-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.

AB - (-)-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.

U2 - 10.1039/c4ob02002b

DO - 10.1039/c4ob02002b

M3 - Article

VL - 12

SP - 9638

EP - 9643

JO - Organic & Biomolecular Chemistry

JF - Organic & Biomolecular Chemistry

SN - 1477-0520

IS - 47

ER -