ArticleProceedings of the National Academy of Sciences of the United States of America2009
Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 146 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
146 citing papers in PubMed, 1 synthesis or guideline pooled it, 284 citations in OpenAlex.
- Clinical Effectiveness of Muscarinic Receptor-Targeted Interventions in Neuropsychiatric Disorders: A Systematic Review.CNS drugs · 2022Pooled it
- Safety, tolerability, pharmacokinetic and pharmacodynamic effects of the muscarinic MAlzheimer's research & therapy · 2025Trial
- Article
- Functional Evaluation of Tetrahydroisoquinoline-Derived Ligands Reveals Distinct Modulatory Profiles at the Muscarinic M1 Receptor.ACS medicinal chemistry letters · 2026Article
- Article
- Targeting muscarinic receptors for treating schizophrenia.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Review
- The Novel Functions of M4 Muscarinic Receptors.Physiological research · 2025Review
- Discovery of VU6052254: A Novel, Potent MACS chemical neuroscience · 2025Article
- Application of Deuterium in an MACS chemical neuroscience · 2025Article
- Unveiling the Interplay: Neurovascular Coupling, Astrocytes and G Protein-Coupled Receptors in Alzheimer's Disease.ACS pharmacology & translational science · 2025Review
- Discovery of VU0467319: an MACS chemical neuroscience · 2025Article
- Novel opportunities for treating complex neuropsychiatric and neurocognitive conditions based on recent developments with xanomeline.Frontiers in psychiatry · 2025Article
- A golden age of muscarinic acetylcholine receptor modulation in neurological diseases.Nature reviews. Drug discovery · 2024Review
- Discovery of VU6007496: Challenges in the Development of an MACS chemical neuroscience · 2024Article
- Allosteric modulators of MScientific reports · 2024Article
- A comprehensive assessment of the cholinergic-supporting and cognitive-enhancing effects of Rosa damascena Mill. (Damask rose) essential oil on scopolamine-induced amnestic rats.Brain and behavior · 2024Article
- Hybrid Allosteric Modulators of M1 Muscarinic Receptors Enhance Acetylcholine Efficacy and Decrease Locomotor Activity and Turning Behaviors in Zebrafish.Research square · 2024Article
- The Partial MACS chemical neuroscience · 2023Article
- The microbiota knows: handling-stress and diet transform the microbial landscape in the gut content of rainbow trout in RAS.Animal microbiome · 2023Article
- MProceedings of the National Academy of Sciences of the United States of America · 2023Article
86 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issuedSeager, Matthew [corrected to Seager, Matthew A]
Authors and funding
29 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The forebrain cholinergic system promotes higher brain function in part by signaling through the M(1) muscarinic acetylcholine receptor (mAChR). During Alzheimer's disease (AD), these cholinergic neurons degenerate, therefore selectively activating M(1) receptors could improve cognitive function in these patients while avoiding unwanted peripheral responses associated with non-selective muscarinic agonists. We describe here benzyl quinolone carboxylic acid (BQCA), a highly selective allosteric potentiator of the M(1) mAChR. BQCA reduces the concentration of ACh required to activate M(1) up to 129-fold with an inflection point value of 845 nM. No potentiation, agonism, or antagonism activity on other mAChRs is observed up to 100 microM. Furthermore studies in M(1)(-/-) mice demonstrates that BQCA requires M(1) to promote inositol phosphate turnover in primary neurons and to increase c-fos and arc RNA expression and ERK phosphorylation in the brain. Radioligand-binding assays, molecular modeling, and site-directed mutagenesis experiments indicate that BQCA acts at an allosteric site involving residues Y179 and W400. BQCA reverses scopolamine-induced memory deficits in contextual fear conditioning, increases blood flow to the cerebral cortex, and increases wakefulness while reducing delta sleep. In contrast to M(1) allosteric agonists, which do not improve memory in scopolamine-challenged mice in contextual fear conditioning, BQCA induces beta-arrestin recruitment to M(1), suggesting a role for this signal transduction mechanism in the cholinergic modulation of memory. In summary, BQCA exploits an allosteric potentiation mechanism to provide selectivity for the M(1) receptor and represents a promising therapeutic strategy for cognitive disorders.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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.