Synthesis and pharmacological evaluation of analogues of benzyl quinolone carboxylic acid (BQCA) designed to bind irreversibly to an allosteric site of the M1 muscarinic acetylcholine receptor

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Abstract

Activation of the M1 muscarinic acetylcholine receptor (mAChR) is a prospective treatment for alleviating cognitive decline experienced in central nervous system (CNS) disorders. Current therapeutics indiscriminately enhance the activity of the endogenous neurotransmitter ACh, leading to side effects. BQCA is a positive allosteric modulator and allosteric agonist at the M1 mAChR that has high subtype selectivity and is a promising template from which to generate higher affinity, more pharmacokinetically viable drug candidates. However, to efficiently guide rational drug design, the binding site of BQCA needs to be conclusively elucidated. We report the synthesis and pharmacological validation of BQCA analogues designed to bind irreversibly to the M1 mAChR. One analogue in particular, 11, can serve as a useful structural probe to confirm the location of the BQCA binding site; ideally, by co-crystallization with the M1 mAChR. Furthermore, this ligand may also be used as a pharmacological tool with a range of applications.
Original languageEnglish
Pages (from-to)5405 - 5418
Number of pages14
JournalJournal of Medicinal Chemistry
Volume57
Issue number12
DOIs
Publication statusPublished - 2014

Cite this

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title = "Synthesis and pharmacological evaluation of analogues of benzyl quinolone carboxylic acid (BQCA) designed to bind irreversibly to an allosteric site of the M1 muscarinic acetylcholine receptor",
abstract = "Activation of the M1 muscarinic acetylcholine receptor (mAChR) is a prospective treatment for alleviating cognitive decline experienced in central nervous system (CNS) disorders. Current therapeutics indiscriminately enhance the activity of the endogenous neurotransmitter ACh, leading to side effects. BQCA is a positive allosteric modulator and allosteric agonist at the M1 mAChR that has high subtype selectivity and is a promising template from which to generate higher affinity, more pharmacokinetically viable drug candidates. However, to efficiently guide rational drug design, the binding site of BQCA needs to be conclusively elucidated. We report the synthesis and pharmacological validation of BQCA analogues designed to bind irreversibly to the M1 mAChR. One analogue in particular, 11, can serve as a useful structural probe to confirm the location of the BQCA binding site; ideally, by co-crystallization with the M1 mAChR. Furthermore, this ligand may also be used as a pharmacological tool with a range of applications.",
author = "Davie, {Briana Jay} and Celine Valant and Jonathan White and Patrick Sexton and Benvenuto Capuano and Arthur Christopoulos and Scammells, {Peter John}",
year = "2014",
doi = "10.1021/jm500556a",
language = "English",
volume = "57",
pages = "5405 -- 5418",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
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T1 - Synthesis and pharmacological evaluation of analogues of benzyl quinolone carboxylic acid (BQCA) designed to bind irreversibly to an allosteric site of the M1 muscarinic acetylcholine receptor

AU - Davie, Briana Jay

AU - Valant, Celine

AU - White, Jonathan

AU - Sexton, Patrick

AU - Capuano, Benvenuto

AU - Christopoulos, Arthur

AU - Scammells, Peter John

PY - 2014

Y1 - 2014

N2 - Activation of the M1 muscarinic acetylcholine receptor (mAChR) is a prospective treatment for alleviating cognitive decline experienced in central nervous system (CNS) disorders. Current therapeutics indiscriminately enhance the activity of the endogenous neurotransmitter ACh, leading to side effects. BQCA is a positive allosteric modulator and allosteric agonist at the M1 mAChR that has high subtype selectivity and is a promising template from which to generate higher affinity, more pharmacokinetically viable drug candidates. However, to efficiently guide rational drug design, the binding site of BQCA needs to be conclusively elucidated. We report the synthesis and pharmacological validation of BQCA analogues designed to bind irreversibly to the M1 mAChR. One analogue in particular, 11, can serve as a useful structural probe to confirm the location of the BQCA binding site; ideally, by co-crystallization with the M1 mAChR. Furthermore, this ligand may also be used as a pharmacological tool with a range of applications.

AB - Activation of the M1 muscarinic acetylcholine receptor (mAChR) is a prospective treatment for alleviating cognitive decline experienced in central nervous system (CNS) disorders. Current therapeutics indiscriminately enhance the activity of the endogenous neurotransmitter ACh, leading to side effects. BQCA is a positive allosteric modulator and allosteric agonist at the M1 mAChR that has high subtype selectivity and is a promising template from which to generate higher affinity, more pharmacokinetically viable drug candidates. However, to efficiently guide rational drug design, the binding site of BQCA needs to be conclusively elucidated. We report the synthesis and pharmacological validation of BQCA analogues designed to bind irreversibly to the M1 mAChR. One analogue in particular, 11, can serve as a useful structural probe to confirm the location of the BQCA binding site; ideally, by co-crystallization with the M1 mAChR. Furthermore, this ligand may also be used as a pharmacological tool with a range of applications.

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DO - 10.1021/jm500556a

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VL - 57

SP - 5405

EP - 5418

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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