ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2010
Molecular mechanisms of action and in vivo validation of an M4 muscarinic acetylcholine receptor allosteric modulator with potential antipsychotic properties.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed, 166 citations in OpenAlex.
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- Next-Generation Analogues of AC265347 as Positive Allosteric Modulators of the Calcium-Sensing Receptor: Pharmacological Investigation of Structural Modifications at the Stereogenic Centre.International journal of molecular sciences · 2025Article
- A golden age of muscarinic acetylcholine receptor modulation in neurological diseases.Nature reviews. Drug discovery · 2024Review
- Discovery of VU6016235: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic MACS chemical neuroscience · 2024Article
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- Design, synthesis and evaluation of novel 2-phenyl-3-(1H-pyrazol-4-yl)pyridine positive allosteric modulators for the MEuropean journal of medicinal chemistry · 2023Article
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- Surface Plasmon Resonance Screening to Identify Active and Selective Adenosine Receptor Binding Fragments.ACS medicinal chemistry letters · 2022Article
- Optimized Administration of the MACS chemical neuroscience · 2022Article
- The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands.Nature communications · 2022Article
- Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders.Biomedicines · 2022Review
- Discovery of structurally distinct tricyclic MBioorganic & medicinal chemistry letters · 2021Article
- Positive allosteric mechanisms of adenosine ANature · 2021Article
- Unusual Oxidative Dimerization in the 3-Aminothieno[2,3-ACS omega · 2021Article
- Update on PET Tracer Development for Muscarinic Acetylcholine Receptors.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Targeting muscarinic receptors to treat schizophrenia.Behavioural brain research · 2021Review
- Restoring Agonist Function at a Chemogenetically Modified MACS chemical neuroscience · 2020Article
- Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics.Pharmaceuticals (Basel, Switzerland) · 2020Review
26 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
We recently identified LY2033298 as a novel allosteric potentiator of acetylcholine (ACh) at the M(4) muscarinic acetylcholine receptor (mAChR). This study characterized the molecular mode of action of this modulator in both recombinant and native systems. Radioligand-binding studies revealed that LY2033298 displayed a preference for the active state of the M(4) mAChR, manifested as a potentiation in the binding affinity of ACh (but not antagonists) and an increase in the proportion of high-affinity agonist-receptor complexes. This property accounted for the robust allosteric agonism displayed by the modulator in recombinant cells in assays of [(35)S]GTPgammaS binding, extracellular regulated kinase 1/2 phosphorylation, glycogen synthase kinase 3beta phosphorylation, and receptor internalization. We also found that the extent of modulation by LY2033298 differed depending on the signaling pathway, indicating that LY2033298 engenders functional selectivity in the actions of ACh. This property was retained in NG108-15 cells, which natively express rodent M(4) mAChRs. Functional interaction studies between LY2033298 and various orthosteric and allosteric ligands revealed that its site of action overlaps with the allosteric site used by prototypical mAChR modulators. Importantly, LY2033298 reduced [(3)H]ACh release from rat striatal slices, indicating retention of its ability to allosterically potentiate endogenous ACh in situ. Moreover, its ability to potentiate oxotremorine-mediated inhibition of condition avoidance responding in rodents was significantly attenuated in M(4) mAChR knockout mice, validating the M(4) mAChR as a key target of action of this novel allosteric ligand.
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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.