ArticleThe Journal of biological chemistry2014
Mechanistic insights into allosteric structure-function relationships at the M1 muscarinic acetylcholine receptor.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 57 citations in OpenAlex.
- Article
- Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.Protein science : a publication of the Protein Society · 2024Review
- Significant pharmacological activities of benzoquinazolines scaffold.Pharmacological reports : PR · 2023Review
- Targeting the M1 muscarinic acetylcholine receptor in Alzheimer's disease.Neuronal signaling · 2022Review
- Multitargeting nature of muscarinic orthosteric agonists and antagonists.Frontiers in physiology · 2022Review
- Development of Novel 4-Arylpyridin-2-one and 6-Arylpyrimidin-4-one Positive Allosteric Modulators of the MChemMedChem · 2021Article
- Restoring Agonist Function at a Chemogenetically Modified MACS chemical neuroscience · 2020Article
- Functional anatomy of the full-length CXCR4-CXCL12 complex systematically dissected by quantitative model-guided mutagenesis.Science signaling · 2020Article
- Structure and selectivity engineering of the MScience (New York, N.Y.) · 2020Article
- Orthosteric muscarinic receptor activation by the insect repellent IR3535 opens new prospects in insecticide-based vector control.Scientific reports · 2020Article
- Current Advances in Allosteric Modulation of Muscarinic Receptors.Biomolecules · 2020Review
- Dynamical important residue network (DIRN): network inference via conformational change.Bioinformatics (Oxford, England) · 2019Article
- Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole.ACS chemical biology · 2019Article
- Cryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs.Nature communications · 2019Article
- 6-Phenylpyrimidin-4-ones as Positive Allosteric Modulators at the MACS chemical neuroscience · 2019Article
- Applications and limitations of fitting of the operational model to determine relative efficacies of agonists.Scientific reports · 2019Article
- Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts.Journal of medicinal chemistry · 2019Review
- Probing the binding site of novel selective positive allosteric modulators at the MBiochemical pharmacology · 2018Article
- Structure-Activity Relationships of Pan-GαACS chemical neuroscience · 2018Article
- Allostery at opioid receptors: modulation with small molecule ligands.British journal of pharmacology · 2018Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Benzylquinolone carboxylic acid (BQCA) is the first highly selective positive allosteric modulator (PAM) for the M1 muscarinic acetylcholine receptor (mAChR), but it possesses low affinity for the allosteric site on the receptor. More recent drug discovery efforts identified 3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo[h]quinazolin-4(3H)-one (referred to herein as benzoquinazolinone 12) as a more potent M1 mAChR PAM with a structural ancestry originating from BQCA and related compounds. In the current study, we optimized the synthesis of and fully characterized the pharmacology of benzoquinazolinone 12, finding that its improved potency derived from a 50-fold increase in allosteric site affinity as compared with BQCA, while retaining a similar level of positive cooperativity with acetylcholine. We then utilized site-directed mutagenesis and molecular modeling to validate the allosteric binding pocket we previously described for BQCA as a shared site for benzoquinazolinone 12 and provide a molecular basis for its improved activity at the M1 mAChR. This includes a key role for hydrophobic and polar interactions with residues Tyr-179, in the second extracellular loop (ECL2) and Trp-400(7.35) in transmembrane domain (TM) 7. Collectively, this study highlights how the properties of affinity and cooperativity can be differentially modified on a common structural scaffold and identifies molecular features that can be exploited to tailor the development of M1 mAChR-targeting PAMs.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.