ArticleMolecular pharmacology2011
Investigation of the molecular mechanism of the α7 nicotinic acetylcholine receptor positive allosteric modulator PNU-120596 provides evidence for two distinct desensitized states.
Article in Molecular pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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76 citing papers in PubMed, 108 citations in OpenAlex.
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- Structural basis for allosteric agonism of human α7 nicotinic acetylcholine receptors.Cell discovery · 2025Article
- Hidden complexity of α7 nicotinic acetylcholine receptor desensitization revealed by MD simulations and Markov state modeling.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Symmetrical Bispyridinium Compounds Act as Open Channel Blockers of Cation-Selective Ion Channels.ACS pharmacology & translational science · 2024Article
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- Pharmacological profiles and anti-inflammatory activity of pCN-diEPP and mCN-diEPP, new alpha9alpha10 nicotinic receptor ligands.Neuropharmacology · 2023Article
- Insights Into the Differential Desensitization ofMolecular pharmacology · 2023Article
- Differential Activation and Desensitization States Promoted by NoncanonicalThe Journal of pharmacology and experimental therapeutics · 2022Article
- An experimental test of the nicotinic hypothesis of COVID-19.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Cannabidiol as a modulator of α7 nicotinic receptors.Cellular and molecular life sciences : CMLS · 2022Article
- Deepening the understanding of CNVs on chromosome 15q11-13 by using hiPSCs: An overview.Frontiers in cell and developmental biology · 2022Review
- Acute effects of the imidacloprid metabolite desnitro-imidacloprid on human nACh receptors relevant for neuronal signaling.Archives of toxicology · 2021Article
- Stable desensitization of αEuropean journal of pharmacology · 2021Article
- The Allosteric Activation of α7 nAChR by α-Conotoxin MrIC Is Modified by Mutations at the Vestibular Site.Toxins · 2021Article
- Therapeutic Targeting ofPharmacological reviews · 2021Review
- Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons.Archives of toxicology · 2021Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
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Abstract
Although α7 nicotinic acetylcholine receptors are considered potentially important therapeutic targets, the development of selective agonists has been stymied by the α7 receptor's intrinsically low probability of opening (P(open)) and the concern that an agonist-based therapeutic approach would disrupt endogenous cholinergic function. Development of α7 positive allosteric modulators (PAMs) holds promise of avoiding both issues. N-(5-Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea (PNU-120596) is one of the most effective α7 PAMs, with a mechanism associated, at least in part, with the destabilization of desensitized states. We studied the mechanism of PNU-120596 potentiation of α7 receptors expressed in Xenopus laevis oocytes and outside-out patches from BOSC 23 cells. We identify two forms of α7 desensitization: one is destabilized by PNU-120596 (D(s)), and the other is induced by strong episodes of activation and is stable in the presence of the PAM (D(i)). Our characterization of prolonged bursts of single-channel currents that occur with PNU-120596 provide a remarkable contrast to the behavior of the channels in the absence of the PAM. Individual channels that avoid the D(i) state show a 100,000-fold increase in P(open) compared with receptors in the nonpotentiated state. In the presence of PNU-120596, balance between D(s) and D(i) is dynamically regulated by both agonist and PAM binding, with maximal ion channel activity at intermediate levels of binding to both classes of sites. In the presence of high agonist concentrations, competitive antagonists may have the effect of shifting the balance in favor of D(s) and increasing ion channel currents.
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