ArticleBritish journal of pharmacology2013
Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor.
Article in British journal of pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
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- Light-Activated Pharmacological Tools for Exploring the Cholinergic System.Medicinal research reviews · 2025Review
- Diazepine Agonists of the 5-HTJournal of medicinal chemistry · 2025Article
- A Sensitive and Selective LC-MS/MS-ESI Method for the Quantitation of Metabolites M9, M12, and M20 of Bexicaserin in Human Plasma and Urine Matrices.Biomedical chromatography : BMC · 2025Article
- Visualizing agonist-induced M2 receptor activation regulated by aromatic ring dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A Highly Sensitive Triple Quad LC-MS/MS Method Development and Validation for the Determination of Bexicaserin (LP352) in Human Plasma and Urine Matrices.Biomedical chromatography : BMC · 2025Article
- Positive allosteric modulation of a GPCR ternary complex.Science advances · 2024Article
- Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator.Nature communications · 2024Article
- Analysing the effect caused by increasing the molecular volume in M1-AChR receptor agonists and antagonists: a structural and computational study.RSC advances · 2024Article
- Subtle Structural Modification of a Synthetic Cannabinoid Receptor Agonist Drastically Increases its Efficacy at the CB1 Receptor.ACS chemical neuroscience · 2023Article
- Carfentanil is a β-arrestin-biased agonist at the μ opioid receptor.British journal of pharmacology · 2023Article
- Article
- Novel Xanomeline-Containing Bitopic Ligands of Muscarinic Acetylcholine Receptors: Design, Synthesis and FRET Investigation.Molecules (Basel, Switzerland) · 2023Article
- Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor.Nature communications · 2023Article
- The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands.Nature communications · 2022Article
- Activation mechanism of the μ-opioid receptor by an allosteric modulator.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders.Biomedicines · 2022Review
- A Dynamic Mass Redistribution Assay for the Human Sweet Taste Receptor Uncovers G-Protein Dependent Biased Ligands.Frontiers in pharmacology · 2022Article
- Fusion with Promiscuous GαInternational journal of molecular sciences · 2021Article
- Control of Brain State Transitions with a Photoswitchable Muscarinic Agonist.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Article
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9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeArtificial agonists may have higher efficacy for receptor activation than the physiological agonist. Until now, such 'superagonism' has rarely been reported for GPCRs. Iperoxo is an extremely potent muscarinic receptor agonist. We hypothesized that iperoxo is a 'superagonist'. EXPERIMENTAL APPROACH: Signalling of iperoxo and newly synthesized structural analogues was compared with that of ACh at label-free M2 muscarinic receptors applying whole cell dynamic mass redistribution, measurement of G-protein activation, evaluation of cell surface agonist binding and computation of operational efficacies. KEY
resultsIn CHO-hM2 cells, iperoxo significantly exceeds ACh in Gi /Gs signalling competence. In the orthosteric loss-of-function mutant M2 -Y104(3.33) A, the maximum effect of iperoxo is hardly compromised in contrast to ACh. 'Superagonism' is preserved in the physiological cellular context of MRC-5 human lung fibroblasts. Structure-signalling relationships including iperoxo derivatives with either modified positively charged head group or altered tail suggest that 'superagonism' of iperoxo is mechanistically based on parallel activation of the receptor protein via two orthosteric interaction points. CONCLUSION AND IMPLICATIONS: Supraphysiological agonist efficacy at muscarinic M2 ACh receptors is demonstrated for the first time. In addition, a possible underlying molecular mechanism of GPCR 'superagonism' is provided. We suggest that iperoxo-like orthosteric GPCR activation is a new avenue towards a novel class of receptor activators.
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