ArticleMolecular pharmacology2009
An allosteric modulator of alpha7 nicotinic receptors, N-(5-Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea (PNU-120596), causes conformational changes in the extracellular ligand binding domain similar to those caused by acetylcholine.
Article in Molecular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 34 citations in OpenAlex.
- Unique Pharmacological Properties of α-Conotoxin OmIA at α7 nAChRs.Frontiers in pharmacology · 2021Article
- More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder.Pharmacological reviews · 2020Review
- Diversity of Nicotinic Acetylcholine Receptor Positive Allosteric Modulators Revealed by Mutagenesis and a Revised Structural Model.Molecular pharmacology · 2018Article
- Calcium imaging with genetically encoded sensor Case12: Facile analysis of α7/α9 nAChR mutants.PloS one · 2017Article
- Classifying neuronal subclasses of the cerebellum through constellation pharmacology.Journal of neurophysiology · 2016Article
- An Unaltered Orthosteric Site and a Network of Long-Range Allosteric Interactions for PNU-120596 in α7 Nicotinic Acetylcholine Receptors.Chemistry & biology · 2015Article
- 6-bromohypaphorine from marine nudibranch mollusk Hermissenda crassicornis is an agonist of human α7 nicotinic acetylcholine receptor.Marine drugs · 2015Article
- Targeting of α7 Nicotinic Acetylcholine Receptors in the Treatment of Schizophrenia and the Use of Auditory Sensory Gating as a Translational Biomarker.Current pharmaceutical design · 2015Review
- ELIC-α7 Nicotinic acetylcholine receptor (α7nAChR) chimeras reveal a prominent role of the extracellular-transmembrane domain interface in allosteric modulation.The Journal of biological chemistry · 2014Article
- The antinociceptive effects of nicotinic receptors α7-positive allosteric modulators in murine acute and tonic pain models.The Journal of pharmacology and experimental therapeutics · 2013Article
- The α7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-120596 both alleviate inflammatory hyperalgesia and cytokine release in the rat.British journal of pharmacology · 2012Article
- α7 nicotinic ACh receptors as a ligand-gated source of Ca(2+) ions: the search for a Ca(2+) optimum.Advances in experimental medicine and biology · 2012Review
- Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations.Biochemical pharmacology · 2011Review
- Single-channel and structural foundations of neuronal α7 acetylcholine receptor potentiation.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2011Article
- The effective opening of nicotinic acetylcholine receptors with single agonist binding sites.The Journal of general physiology · 2011Article
- Cysteine accessibility analysis of the human alpha7 nicotinic acetylcholine receptor ligand-binding domain identifies L119 as a gatekeeper.Neuropharmacology · 2011Article
- Tethered agonist analogs as site-specific probes for domains of the human α7 nicotinic acetylcholine receptor that differentially regulate activation and desensitization.Molecular pharmacology · 2010Article
- Article
- Mechanism of Allosteric Modulation of the Cys-loop Receptors.Pharmaceuticals (Basel, Switzerland) · 2010Review
- Physiological concentrations of choline activate native alpha7-containing nicotinic acetylcholine receptors in the presence of PNU-120596 [1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)-urea].The Journal of pharmacology and experimental therapeutics · 2010Article
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5 authors at 1 institution in 1 country.
Funding
Abstract
Nicotinic acetylcholine receptors are implicated in several neuropsychiatric disorders, including nicotine addiction, Alzheimer's, schizophrenia, and depression. Therefore, they represent a critical molecular target for drug development and targeted therapeutic intervention. Understanding the molecular mechanisms by which allosteric modulators enhance activation of these receptors is crucial to the development of new drugs. We used the substituted cysteine accessibility method to study conformational changes induced by the positive allosteric modulator N-(5-chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea (PNU-120596) in the extracellular ligand binding domain of alpha7 nicotinic receptors carrying the L247T mutation. PNU-120596 caused changes in cysteine accessibility at the inner beta sheet, transition zone, and agonist binding site. These changes in accessibility are similar to but not identical to those caused by ACh alone. In particular, PNU-120596 induced changes in MTSEA accessibility at N170C (in the transition zone) that were substantially different from those evoked by acetylcholine (ACh). We found that PNU-120596 induced changes at position E172C in the absence of allosteric modulation. We identified a cysteine mutation of the agonist binding site (W148C) that exhibited an unexpected phenotype in which PNU-120596 acts as a full agonist. In this mutant, ACh-evoked currents were more sensitive to thiol modification than PNU-evoked currents, suggesting that PNU-120596 does not bind at unoccupied agonist-binding sites. Our results provide evidence that binding sites for PNU-120596 are not in the agonist-binding sites and demonstrate that positive allosteric modulators such as PNU-120596 enhance agonist-evoked gating of nicotinic receptors by eliciting conformational effects that are similar but nonidentical to the gating conformations promoted by ACh.
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