Discovery of 2-Methyl-5-(1H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M4 mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders

Boqun Liu; Geoff Thompson; Manuela Jörg; Nicholas Barnes; David M. Thal; Arthur Christopoulos; Ben Capuano; Celine Valant; Peter J. Scammells

doi:10.1021/acs.jmedchem.4c01207

Discovery of 2-Methyl-5-(1H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M₄ mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders

Boqun Liu, Geoff Thompson, Manuela Jörg, Nicholas Barnes, David M. Thal, Arthur Christopoulos, Ben Capuano, Celine Valant, Peter J. Scammells

Research output: Contribution to journal › Article › Research › peer-review

Abstract

The M₄ muscarinic acetylcholine receptor (mAChR) is a biological target for neurocognitive disorders. Compound 1 is an ago-PAM for the M₄ mAChR. Herein, we report the design, synthesis, and evaluation of novel putative M₄ mAChR PAMs based on 1. These analogs were screened and then fully characterized in two functional assays (G_oB protein activation and CAMYEL activation) to quantify their allosteric and ago-PAM properties against ACh. A selection of 7 M₄ PAMs were assessed for their ability to modulate ACh-mediated β-arrestin recruitment and revealed 4 distinct clusters of M₄ PAM activity: (1) analogs similar to 1 (24d), (2) analogs demonstrating only allosteric agonism (23d), (3) analogs with increased allosteric properties in CAMYEL activation (23b/23f and 24a/24b), and (4) analogs with a biased modulatory effect toward β-arrestin recruitment (23i). These novel M₄ chemical tools disclose discrete molecular determinants, allowing further interrogation of the therapeutic roles of cAMP and β-arrestin pathways in neurocognitive disorders.

Original language	English
Pages (from-to)	13286–13304
Number of pages	19
Journal	Journal of Medicinal Chemistry
Volume	67
Issue number	15
DOIs	https://doi.org/10.1021/acs.jmedchem.4c01207
Publication status	Published - 18 Jul 2024

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10.1021/acs.jmedchem.4c01207

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Liu, B., Thompson, G., Jörg, M., Barnes, N., Thal, D. M., Christopoulos, A., Capuano, B., Valant, C., & Scammells, P. J. (2024). Discovery of 2-Methyl-5-(1H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M₄ mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders. Journal of Medicinal Chemistry, 67(15), 13286–13304. https://doi.org/10.1021/acs.jmedchem.4c01207

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title = "Discovery of 2-Methyl-5-(1H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M4 mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders",

abstract = "The M4 muscarinic acetylcholine receptor (mAChR) is a biological target for neurocognitive disorders. Compound 1 is an ago-PAM for the M4 mAChR. Herein, we report the design, synthesis, and evaluation of novel putative M4 mAChR PAMs based on 1. These analogs were screened and then fully characterized in two functional assays (GoB protein activation and CAMYEL activation) to quantify their allosteric and ago-PAM properties against ACh. A selection of 7 M4 PAMs were assessed for their ability to modulate ACh-mediated β-arrestin recruitment and revealed 4 distinct clusters of M4 PAM activity: (1) analogs similar to 1 (24d), (2) analogs demonstrating only allosteric agonism (23d), (3) analogs with increased allosteric properties in CAMYEL activation (23b/23f and 24a/24b), and (4) analogs with a biased modulatory effect toward β-arrestin recruitment (23i). These novel M4 chemical tools disclose discrete molecular determinants, allowing further interrogation of the therapeutic roles of cAMP and β-arrestin pathways in neurocognitive disorders.",

author = "Boqun Liu and Geoff Thompson and Manuela J{\"o}rg and Nicholas Barnes and Thal, {David M.} and Arthur Christopoulos and Ben Capuano and Celine Valant and Scammells, {Peter J.}",

note = "Publisher Copyright: {\textcopyright} 2024 American Chemical Society.",

year = "2024",

month = jul,

day = "18",

doi = "10.1021/acs.jmedchem.4c01207",

language = "English",

volume = "67",

pages = "13286–13304",

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Liu, B, Thompson, G, Jörg, M, Barnes, N, Thal, DM , Christopoulos, A , Capuano, B , Valant, C & Scammells, PJ 2024, 'Discovery of 2-Methyl-5-(1H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M₄ mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders', Journal of Medicinal Chemistry, vol. 67, no. 15, pp. 13286–13304. https://doi.org/10.1021/acs.jmedchem.4c01207

Discovery of 2-Methyl-5-(1H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M₄ mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders. / Liu, Boqun; Thompson, Geoff; Jörg, Manuela et al.
In: Journal of Medicinal Chemistry, Vol. 67, No. 15, 18.07.2024, p. 13286–13304.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Discovery of 2-Methyl-5-(1H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M4 mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders

AU - Liu, Boqun

AU - Thompson, Geoff

AU - Jörg, Manuela

AU - Barnes, Nicholas

AU - Thal, David M.

AU - Christopoulos, Arthur

AU - Capuano, Ben

AU - Valant, Celine

AU - Scammells, Peter J.

PY - 2024/7/18

Y1 - 2024/7/18

N2 - The M4 muscarinic acetylcholine receptor (mAChR) is a biological target for neurocognitive disorders. Compound 1 is an ago-PAM for the M4 mAChR. Herein, we report the design, synthesis, and evaluation of novel putative M4 mAChR PAMs based on 1. These analogs were screened and then fully characterized in two functional assays (GoB protein activation and CAMYEL activation) to quantify their allosteric and ago-PAM properties against ACh. A selection of 7 M4 PAMs were assessed for their ability to modulate ACh-mediated β-arrestin recruitment and revealed 4 distinct clusters of M4 PAM activity: (1) analogs similar to 1 (24d), (2) analogs demonstrating only allosteric agonism (23d), (3) analogs with increased allosteric properties in CAMYEL activation (23b/23f and 24a/24b), and (4) analogs with a biased modulatory effect toward β-arrestin recruitment (23i). These novel M4 chemical tools disclose discrete molecular determinants, allowing further interrogation of the therapeutic roles of cAMP and β-arrestin pathways in neurocognitive disorders.

AB - The M4 muscarinic acetylcholine receptor (mAChR) is a biological target for neurocognitive disorders. Compound 1 is an ago-PAM for the M4 mAChR. Herein, we report the design, synthesis, and evaluation of novel putative M4 mAChR PAMs based on 1. These analogs were screened and then fully characterized in two functional assays (GoB protein activation and CAMYEL activation) to quantify their allosteric and ago-PAM properties against ACh. A selection of 7 M4 PAMs were assessed for their ability to modulate ACh-mediated β-arrestin recruitment and revealed 4 distinct clusters of M4 PAM activity: (1) analogs similar to 1 (24d), (2) analogs demonstrating only allosteric agonism (23d), (3) analogs with increased allosteric properties in CAMYEL activation (23b/23f and 24a/24b), and (4) analogs with a biased modulatory effect toward β-arrestin recruitment (23i). These novel M4 chemical tools disclose discrete molecular determinants, allowing further interrogation of the therapeutic roles of cAMP and β-arrestin pathways in neurocognitive disorders.

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U2 - 10.1021/acs.jmedchem.4c01207

DO - 10.1021/acs.jmedchem.4c01207

M3 - Article

AN - SCOPUS:85199085676

SN - 0022-2623

VL - 67

SP - 13286

EP - 13304

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 15

ER -

Discovery of 2-Methyl-5-(1H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M₄ mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders

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Discovery of 2-Methyl-5-(1H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M4 mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders

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ARC Industrial Transformation Training Centre for Cryo-Electron Microscopy of Membrane Proteins for Drug Discovery

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Discovery of 2-Methyl-5-(1H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M₄ mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders