Synthesis and Pharmacological Evaluation of Heterocyclic Carboxamides: Positive Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor with Weak Agonist Activity and Diverse Modulatory Profiles

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Abstract

Targeting allosteric sites at M1 muscarinic acetylcholine receptors is a promising strategy for the treatment of Alzheimer's disease. Positive allosteric modulators not only may potentiate binding and/or signaling of the endogenous agonist acetylcholine (ACh) but also may possess direct agonist activity (thus referred to as PAM-agonists). Recent studies suggest that PAM-agonists with robust intrinsic efficacy are more likely to produce adverse effects in vivo. Herein we present the synthesis and pharmacological evaluation of a series of pyrrole-3-carboxamides with a diverse range of allosteric profiles. We proposed structural modifications at top, core, or pendant moieties of a prototypical molecule. Although generally there was a correlation between the degree of agonist activity and the modulatory potency of the PAMs, some derivatives displayed weak intrinsic efficacy yet maintained strong allosteric modulation. We also identified molecules with the ability to potentiate mainly the affinity or both affinity and efficacy of ACh.

Original languageEnglish
Pages (from-to)2875-2894
Number of pages20
JournalJournal of Medicinal Chemistry
Volume61
Issue number7
DOIs
Publication statusPublished - 12 Apr 2018

Cite this

@article{d249293d423e4e38a6dc05948d2976a6,
title = "Synthesis and Pharmacological Evaluation of Heterocyclic Carboxamides: Positive Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor with Weak Agonist Activity and Diverse Modulatory Profiles",
abstract = "Targeting allosteric sites at M1 muscarinic acetylcholine receptors is a promising strategy for the treatment of Alzheimer's disease. Positive allosteric modulators not only may potentiate binding and/or signaling of the endogenous agonist acetylcholine (ACh) but also may possess direct agonist activity (thus referred to as PAM-agonists). Recent studies suggest that PAM-agonists with robust intrinsic efficacy are more likely to produce adverse effects in vivo. Herein we present the synthesis and pharmacological evaluation of a series of pyrrole-3-carboxamides with a diverse range of allosteric profiles. We proposed structural modifications at top, core, or pendant moieties of a prototypical molecule. Although generally there was a correlation between the degree of agonist activity and the modulatory potency of the PAMs, some derivatives displayed weak intrinsic efficacy yet maintained strong allosteric modulation. We also identified molecules with the ability to potentiate mainly the affinity or both affinity and efficacy of ACh.",
author = "Dallagnol, {Juliana C.C.} and Elham Khajehali and {Van Der Westhuizen}, {Emma T.} and Manuela J{\"o}rg and Celine Valant and Gon{\cc}alves, {Alan G.} and Ben Capuano and Arthur Christopoulos and Scammells, {Peter J.}",
year = "2018",
month = "4",
day = "12",
doi = "10.1021/acs.jmedchem.7b01812",
language = "English",
volume = "61",
pages = "2875--2894",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "7",

}

TY - JOUR

T1 - Synthesis and Pharmacological Evaluation of Heterocyclic Carboxamides

T2 - Positive Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor with Weak Agonist Activity and Diverse Modulatory Profiles

AU - Dallagnol, Juliana C.C.

AU - Khajehali, Elham

AU - Van Der Westhuizen, Emma T.

AU - Jörg, Manuela

AU - Valant, Celine

AU - Gonçalves, Alan G.

AU - Capuano, Ben

AU - Christopoulos, Arthur

AU - Scammells, Peter J.

PY - 2018/4/12

Y1 - 2018/4/12

N2 - Targeting allosteric sites at M1 muscarinic acetylcholine receptors is a promising strategy for the treatment of Alzheimer's disease. Positive allosteric modulators not only may potentiate binding and/or signaling of the endogenous agonist acetylcholine (ACh) but also may possess direct agonist activity (thus referred to as PAM-agonists). Recent studies suggest that PAM-agonists with robust intrinsic efficacy are more likely to produce adverse effects in vivo. Herein we present the synthesis and pharmacological evaluation of a series of pyrrole-3-carboxamides with a diverse range of allosteric profiles. We proposed structural modifications at top, core, or pendant moieties of a prototypical molecule. Although generally there was a correlation between the degree of agonist activity and the modulatory potency of the PAMs, some derivatives displayed weak intrinsic efficacy yet maintained strong allosteric modulation. We also identified molecules with the ability to potentiate mainly the affinity or both affinity and efficacy of ACh.

AB - Targeting allosteric sites at M1 muscarinic acetylcholine receptors is a promising strategy for the treatment of Alzheimer's disease. Positive allosteric modulators not only may potentiate binding and/or signaling of the endogenous agonist acetylcholine (ACh) but also may possess direct agonist activity (thus referred to as PAM-agonists). Recent studies suggest that PAM-agonists with robust intrinsic efficacy are more likely to produce adverse effects in vivo. Herein we present the synthesis and pharmacological evaluation of a series of pyrrole-3-carboxamides with a diverse range of allosteric profiles. We proposed structural modifications at top, core, or pendant moieties of a prototypical molecule. Although generally there was a correlation between the degree of agonist activity and the modulatory potency of the PAMs, some derivatives displayed weak intrinsic efficacy yet maintained strong allosteric modulation. We also identified molecules with the ability to potentiate mainly the affinity or both affinity and efficacy of ACh.

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U2 - 10.1021/acs.jmedchem.7b01812

DO - 10.1021/acs.jmedchem.7b01812

M3 - Article

VL - 61

SP - 2875

EP - 2894

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 7

ER -