Development of a photoactivatable allosteric ligand for the M1 muscarinic acetylcholine receptor

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The field of G protein-coupled receptor drug discovery has benefited greatly from the structural and functional insights afforded by photoactivatable ligands. One G protein-coupled receptor subfamily for which photoactivatable ligands have been developed is the muscarinic acetylcholine receptor family, though, to date, all such ligands have been designed to target the orthosteric (endogenous ligand) binding site of these receptors. Herein we report the synthesis and pharmacological investigation of a novel photoaffinity label, MIPS1455 (4), designed to bind irreversibly to an allosteric site of the M1 muscarinic acetylcholine receptor; a target of therapeutic interest for the treatment of cognitive deficits. MIPS1455 may be a valuable molecular tool for further investigating allosteric interactions at this receptor.
Original languageEnglish
Pages (from-to)902 - 907
Number of pages6
JournalACS Chemical Neuroscience
Volume5
Issue number10
DOIs
Publication statusPublished - 2014

Cite this

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title = "Development of a photoactivatable allosteric ligand for the M1 muscarinic acetylcholine receptor",
abstract = "The field of G protein-coupled receptor drug discovery has benefited greatly from the structural and functional insights afforded by photoactivatable ligands. One G protein-coupled receptor subfamily for which photoactivatable ligands have been developed is the muscarinic acetylcholine receptor family, though, to date, all such ligands have been designed to target the orthosteric (endogenous ligand) binding site of these receptors. Herein we report the synthesis and pharmacological investigation of a novel photoaffinity label, MIPS1455 (4), designed to bind irreversibly to an allosteric site of the M1 muscarinic acetylcholine receptor; a target of therapeutic interest for the treatment of cognitive deficits. MIPS1455 may be a valuable molecular tool for further investigating allosteric interactions at this receptor.",
author = "Davie, {Briana Jay} and Patrick Sexton and Benvenuto Capuano and Arthur Christopoulos and Scammells, {Peter John}",
year = "2014",
doi = "10.1021/cn500173x",
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journal = "ACS Chemical Neuroscience",
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Development of a photoactivatable allosteric ligand for the M1 muscarinic acetylcholine receptor. / Davie, Briana Jay; Sexton, Patrick; Capuano, Benvenuto; Christopoulos, Arthur; Scammells, Peter John.

In: ACS Chemical Neuroscience, Vol. 5, No. 10, 2014, p. 902 - 907.

Research output: Contribution to journalArticleResearchpeer-review

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AB - The field of G protein-coupled receptor drug discovery has benefited greatly from the structural and functional insights afforded by photoactivatable ligands. One G protein-coupled receptor subfamily for which photoactivatable ligands have been developed is the muscarinic acetylcholine receptor family, though, to date, all such ligands have been designed to target the orthosteric (endogenous ligand) binding site of these receptors. Herein we report the synthesis and pharmacological investigation of a novel photoaffinity label, MIPS1455 (4), designed to bind irreversibly to an allosteric site of the M1 muscarinic acetylcholine receptor; a target of therapeutic interest for the treatment of cognitive deficits. MIPS1455 may be a valuable molecular tool for further investigating allosteric interactions at this receptor.

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