Development of a photoactivatable allosteric ligand for the m1 muscarinic acetylcholine receptor

Briana J Davie; Patrick M Sexton; Ben Capuano; Arthur Christopoulos; Peter J Scammells

doi:10.1021/cn500173x

Development of a photoactivatable allosteric ligand for the m1 muscarinic acetylcholine receptor

ACS Chem Neurosci. 2014 Oct 15;5(10):902-7. doi: 10.1021/cn500173x. Epub 2014 Sep 9.

Authors

Briana J Davie¹, Patrick M Sexton, Ben Capuano, Arthur Christopoulos, Peter J Scammells

Affiliation

¹ Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.

PMID: 25188871
DOI: 10.1021/cn500173x

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.

Keywords: BQCA; Muscarinic; allosteric; cognition; photoactivatable; photoaffinity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Site
Animals
Benzophenones / chemical synthesis*
Benzophenones / metabolism
Benzophenones / pharmacology*
CHO Cells
Cholinergic Agents / chemistry
Cholinergic Agents / metabolism
Cholinergic Agents / pharmacology
Chromatography, High Pressure Liquid
Chromatography, Liquid
Cricetulus
Dose-Response Relationship, Drug
Humans
Ligands
Magnetic Resonance Spectroscopy
Mass Spectrometry
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Phosphorylation / drug effects
Photoaffinity Labels / chemical synthesis*
Photoaffinity Labels / metabolism
Photoaffinity Labels / pharmacology*
Photolysis
Quinolones / chemical synthesis*
Quinolones / metabolism
Quinolones / pharmacology*
Receptor, Muscarinic M1 / metabolism*
Ultraviolet Rays

Substances

1-(4-benzoylbenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Benzophenones
Cholinergic Agents
Ligands
Photoaffinity Labels
Quinolones
Receptor, Muscarinic M1
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3