Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M{1} muscarinic receptor

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Abstract

Established therapy in Alzheimer s disease centres on potentiation of the endogenous orthosteric ligand, acetylcholine, at the M1 muscarinic receptors found in higher concentrations in the cortical and hippocampal brain regions. Unfortunately, such therapy invariably suffers from undesirable effects, in part due to indiscriminate activation of other members of the muscarinic receptor family. Due to high sequence conservation in the orthosteric binding site across these receptors, to date, development of a truly M1 selective agonist has not been achieved. M1 muscarinic positive allosteric modulators/allosteric agonists such as BQCA offer an attractive solution to this problem, being exquisitely M1 selective over other muscarinic subtypes and exhibiting a saturable effect, thus reducing problems associated with overdosing. A common difficulty with allosteric ligands is interpreting SAR, based on all-encompassing allosteric potency values derived from modulator titration curves established against a fixed concentration of agonist. In reality these potency values are made up of multiple pharmacological parameters - each potentially, and differentially sensitive to structural modification of the ligand. Herein, we report a novel series of BQCA analogues bearing a variety of structural modifications which appear to augment ligand affinity for the receptor (pKB), intrinsic efficacy (tauB) and both binding (alpha) and functional (beta) cooperativity with the orthosteric ligand acetylcholine. Ultimately, development of such enriched SAR surrounding allosteric modulators is anticipated to provide a more thorough mechanistic explanation for their mode of action, and ultimately allow tailored allosteric ligands to be developed.
Original languageEnglish
Pages (from-to)5151 - 5172
Number of pages22
JournalJournal of Medicinal Chemistry
Volume56
Issue number12
DOIs
Publication statusPublished - 2013

Cite this

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title = "Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M{1} muscarinic receptor",
abstract = "Established therapy in Alzheimer s disease centres on potentiation of the endogenous orthosteric ligand, acetylcholine, at the M1 muscarinic receptors found in higher concentrations in the cortical and hippocampal brain regions. Unfortunately, such therapy invariably suffers from undesirable effects, in part due to indiscriminate activation of other members of the muscarinic receptor family. Due to high sequence conservation in the orthosteric binding site across these receptors, to date, development of a truly M1 selective agonist has not been achieved. M1 muscarinic positive allosteric modulators/allosteric agonists such as BQCA offer an attractive solution to this problem, being exquisitely M1 selective over other muscarinic subtypes and exhibiting a saturable effect, thus reducing problems associated with overdosing. A common difficulty with allosteric ligands is interpreting SAR, based on all-encompassing allosteric potency values derived from modulator titration curves established against a fixed concentration of agonist. In reality these potency values are made up of multiple pharmacological parameters - each potentially, and differentially sensitive to structural modification of the ligand. Herein, we report a novel series of BQCA analogues bearing a variety of structural modifications which appear to augment ligand affinity for the receptor (pKB), intrinsic efficacy (tauB) and both binding (alpha) and functional (beta) cooperativity with the orthosteric ligand acetylcholine. Ultimately, development of such enriched SAR surrounding allosteric modulators is anticipated to provide a more thorough mechanistic explanation for their mode of action, and ultimately allow tailored allosteric ligands to be developed.",
author = "Mistry, {Shailesh Natvarbhai} and Celine Valant and Patrick Sexton and Benvenuto Capuano and Arthur Christopoulos and Scammells, {Peter John}",
year = "2013",
doi = "10.1021/jm400540b",
language = "English",
volume = "56",
pages = "5151 -- 5172",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "12",

}

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T1 - Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M{1} muscarinic receptor

AU - Mistry, Shailesh Natvarbhai

AU - Valant, Celine

AU - Sexton, Patrick

AU - Capuano, Benvenuto

AU - Christopoulos, Arthur

AU - Scammells, Peter John

PY - 2013

Y1 - 2013

N2 - Established therapy in Alzheimer s disease centres on potentiation of the endogenous orthosteric ligand, acetylcholine, at the M1 muscarinic receptors found in higher concentrations in the cortical and hippocampal brain regions. Unfortunately, such therapy invariably suffers from undesirable effects, in part due to indiscriminate activation of other members of the muscarinic receptor family. Due to high sequence conservation in the orthosteric binding site across these receptors, to date, development of a truly M1 selective agonist has not been achieved. M1 muscarinic positive allosteric modulators/allosteric agonists such as BQCA offer an attractive solution to this problem, being exquisitely M1 selective over other muscarinic subtypes and exhibiting a saturable effect, thus reducing problems associated with overdosing. A common difficulty with allosteric ligands is interpreting SAR, based on all-encompassing allosteric potency values derived from modulator titration curves established against a fixed concentration of agonist. In reality these potency values are made up of multiple pharmacological parameters - each potentially, and differentially sensitive to structural modification of the ligand. Herein, we report a novel series of BQCA analogues bearing a variety of structural modifications which appear to augment ligand affinity for the receptor (pKB), intrinsic efficacy (tauB) and both binding (alpha) and functional (beta) cooperativity with the orthosteric ligand acetylcholine. Ultimately, development of such enriched SAR surrounding allosteric modulators is anticipated to provide a more thorough mechanistic explanation for their mode of action, and ultimately allow tailored allosteric ligands to be developed.

AB - Established therapy in Alzheimer s disease centres on potentiation of the endogenous orthosteric ligand, acetylcholine, at the M1 muscarinic receptors found in higher concentrations in the cortical and hippocampal brain regions. Unfortunately, such therapy invariably suffers from undesirable effects, in part due to indiscriminate activation of other members of the muscarinic receptor family. Due to high sequence conservation in the orthosteric binding site across these receptors, to date, development of a truly M1 selective agonist has not been achieved. M1 muscarinic positive allosteric modulators/allosteric agonists such as BQCA offer an attractive solution to this problem, being exquisitely M1 selective over other muscarinic subtypes and exhibiting a saturable effect, thus reducing problems associated with overdosing. A common difficulty with allosteric ligands is interpreting SAR, based on all-encompassing allosteric potency values derived from modulator titration curves established against a fixed concentration of agonist. In reality these potency values are made up of multiple pharmacological parameters - each potentially, and differentially sensitive to structural modification of the ligand. Herein, we report a novel series of BQCA analogues bearing a variety of structural modifications which appear to augment ligand affinity for the receptor (pKB), intrinsic efficacy (tauB) and both binding (alpha) and functional (beta) cooperativity with the orthosteric ligand acetylcholine. Ultimately, development of such enriched SAR surrounding allosteric modulators is anticipated to provide a more thorough mechanistic explanation for their mode of action, and ultimately allow tailored allosteric ligands to be developed.

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