6-Phenylpyrimidin-4-ones as Positive Allosteric Modulators at the M1 mAChR

The Determinants of Allosteric Activity

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Targeting allosteric sites of the M 1 muscarinic acetylcholine receptor (mAChR) is an enticing approach to overcome the lack of receptor subtype selectivity observed with orthosteric ligands. This is a promising strategy for obtaining novel therapeutics to treat cognitive deficits observed in Alzheimer's disease and schizophrenia, while reducing the peripheral side effects such as seen in the current treatment regimes, which are non-subtype selective. We previously described compound 2, the first positive allosteric modulator (PAM) of the M 1 mAChR based on a 6-phenylpyrimidin-4-one scaffold, which has been further developed in this study. Herein, we present the synthesis, characterization, and pharmacological evaluation of a series of 6-phenylpyrimidin-4-ones with modifications to the 4-(1-methylpyrazol-4-yl)benzyl pendant. Selected compounds, BQCA, 1, 2, 9i, 13, 14b, 15c, and 15d, were further profiled in terms of their allosteric affinity, cooperativity with acetylcholine (ACh), and intrinsic efficacy. Additionally, 2 and 9i were tested in mouse primary cortical neurons, displaying various degrees of intrinsic agonism and potentiation of the acetylcholine response. Overall, the results suggest that the pendant moiety is important for allosteric binding affinity and the direct agonistic efficacy of the 6-phenylpyrimidin-4-one based M 1 mAChR PAMs.

Original languageEnglish
Pages (from-to)1099-1114
Number of pages16
JournalACS Chemical Neuroscience
Volume10
Issue number3
DOIs
Publication statusPublished - 20 Mar 2019

Keywords

  • Alzheimer's disease
  • BQCA
  • M muscarinic acetylcholine receptor
  • positive allosteric modulator
  • pyrimidinones
  • schizophrenia

Cite this

@article{bbf4774af0cf4c4a8c5a73ee770b48ab,
title = "6-Phenylpyrimidin-4-ones as Positive Allosteric Modulators at the M1 mAChR: The Determinants of Allosteric Activity",
abstract = "Targeting allosteric sites of the M 1 muscarinic acetylcholine receptor (mAChR) is an enticing approach to overcome the lack of receptor subtype selectivity observed with orthosteric ligands. This is a promising strategy for obtaining novel therapeutics to treat cognitive deficits observed in Alzheimer's disease and schizophrenia, while reducing the peripheral side effects such as seen in the current treatment regimes, which are non-subtype selective. We previously described compound 2, the first positive allosteric modulator (PAM) of the M 1 mAChR based on a 6-phenylpyrimidin-4-one scaffold, which has been further developed in this study. Herein, we present the synthesis, characterization, and pharmacological evaluation of a series of 6-phenylpyrimidin-4-ones with modifications to the 4-(1-methylpyrazol-4-yl)benzyl pendant. Selected compounds, BQCA, 1, 2, 9i, 13, 14b, 15c, and 15d, were further profiled in terms of their allosteric affinity, cooperativity with acetylcholine (ACh), and intrinsic efficacy. Additionally, 2 and 9i were tested in mouse primary cortical neurons, displaying various degrees of intrinsic agonism and potentiation of the acetylcholine response. Overall, the results suggest that the pendant moiety is important for allosteric binding affinity and the direct agonistic efficacy of the 6-phenylpyrimidin-4-one based M 1 mAChR PAMs.",
keywords = "Alzheimer's disease, BQCA, M muscarinic acetylcholine receptor, positive allosteric modulator, pyrimidinones, schizophrenia",
author = "Jorg, {Manuela Therese} and {van der Westhuizen}, {Emma T} and Elham Khajehali and Burger, {Wessel Alexander Christian} and Jonathan White and Choy, {Kwok Ho Christopher} and Tobin, {Andrew B.} and Sexton, {Patrick Michael} and Celine Valant and Benvenuto Capuano and Arthur Christopoulos and Scammells, {Peter John}",
year = "2019",
month = "3",
day = "20",
doi = "10.1021/acschemneuro.8b00613",
language = "English",
volume = "10",
pages = "1099--1114",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
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T1 - 6-Phenylpyrimidin-4-ones as Positive Allosteric Modulators at the M1 mAChR

T2 - The Determinants of Allosteric Activity

AU - Jorg, Manuela Therese

AU - van der Westhuizen, Emma T

AU - Khajehali, Elham

AU - Burger, Wessel Alexander Christian

AU - White, Jonathan

AU - Choy, Kwok Ho Christopher

AU - Tobin, Andrew B.

AU - Sexton, Patrick Michael

AU - Valant, Celine

AU - Capuano, Benvenuto

AU - Christopoulos, Arthur

AU - Scammells, Peter John

PY - 2019/3/20

Y1 - 2019/3/20

N2 - Targeting allosteric sites of the M 1 muscarinic acetylcholine receptor (mAChR) is an enticing approach to overcome the lack of receptor subtype selectivity observed with orthosteric ligands. This is a promising strategy for obtaining novel therapeutics to treat cognitive deficits observed in Alzheimer's disease and schizophrenia, while reducing the peripheral side effects such as seen in the current treatment regimes, which are non-subtype selective. We previously described compound 2, the first positive allosteric modulator (PAM) of the M 1 mAChR based on a 6-phenylpyrimidin-4-one scaffold, which has been further developed in this study. Herein, we present the synthesis, characterization, and pharmacological evaluation of a series of 6-phenylpyrimidin-4-ones with modifications to the 4-(1-methylpyrazol-4-yl)benzyl pendant. Selected compounds, BQCA, 1, 2, 9i, 13, 14b, 15c, and 15d, were further profiled in terms of their allosteric affinity, cooperativity with acetylcholine (ACh), and intrinsic efficacy. Additionally, 2 and 9i were tested in mouse primary cortical neurons, displaying various degrees of intrinsic agonism and potentiation of the acetylcholine response. Overall, the results suggest that the pendant moiety is important for allosteric binding affinity and the direct agonistic efficacy of the 6-phenylpyrimidin-4-one based M 1 mAChR PAMs.

AB - Targeting allosteric sites of the M 1 muscarinic acetylcholine receptor (mAChR) is an enticing approach to overcome the lack of receptor subtype selectivity observed with orthosteric ligands. This is a promising strategy for obtaining novel therapeutics to treat cognitive deficits observed in Alzheimer's disease and schizophrenia, while reducing the peripheral side effects such as seen in the current treatment regimes, which are non-subtype selective. We previously described compound 2, the first positive allosteric modulator (PAM) of the M 1 mAChR based on a 6-phenylpyrimidin-4-one scaffold, which has been further developed in this study. Herein, we present the synthesis, characterization, and pharmacological evaluation of a series of 6-phenylpyrimidin-4-ones with modifications to the 4-(1-methylpyrazol-4-yl)benzyl pendant. Selected compounds, BQCA, 1, 2, 9i, 13, 14b, 15c, and 15d, were further profiled in terms of their allosteric affinity, cooperativity with acetylcholine (ACh), and intrinsic efficacy. Additionally, 2 and 9i were tested in mouse primary cortical neurons, displaying various degrees of intrinsic agonism and potentiation of the acetylcholine response. Overall, the results suggest that the pendant moiety is important for allosteric binding affinity and the direct agonistic efficacy of the 6-phenylpyrimidin-4-one based M 1 mAChR PAMs.

KW - Alzheimer's disease

KW - BQCA

KW - M muscarinic acetylcholine receptor

KW - positive allosteric modulator

KW - pyrimidinones

KW - schizophrenia

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U2 - 10.1021/acschemneuro.8b00613

DO - 10.1021/acschemneuro.8b00613

M3 - Article

VL - 10

SP - 1099

EP - 1114

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 3

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