ArticleThe Journal of pharmacology and experimental therapeutics2014
The minimal pharmacophore for silent agonism of the α7 nicotinic acetylcholine receptor.
Article in The Journal of pharmacology and experimental therapeutics, 2014. 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 36 papers.
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Who cites it
36 citing papers in PubMed, 45 citations in OpenAlex.
- Putative α7-selective ligands interact with α9-containing nicotinic acetylcholine receptors and modulate immune functions of human mononuclear phagocytes.Frontiers in immunology · 2026Article
- The Functional Topology of Phenylpiperazinium Agonists and Antagonists on the Nicotinic Acetylcholine Receptor Landscape: Pointing the Way for Future Therapeutic Management of Inflammation and Neuropathic Pain.ACS chemical neuroscience · 2025Article
- Explorations of Agonist Selectivity for the α9* nAChR with Novel Substituted Carbamoyl/Amido/Heteroaryl Dialkylpiperazinium Salts and Their Therapeutic Implications in Pain and Inflammation.Journal of medicinal chemistry · 2024Article
- Article
- Insights Into the Differential Desensitization ofMolecular pharmacology · 2023Article
- Coffee and cigarettes: Modulation of high and low sensitivity α4β2 nicotinic acetylcholine receptors by n-MP, a biomarker of coffee consumption.Neuropharmacology · 2022Article
- Dual effects of supplemental oxygen on pulmonary infection, inflammatory lung injury, and neuromodulation in aging and COVID-19.Free radical biology & medicine · 2022Review
- Targeting α7 nicotinic acetylcholine receptors for chronic pain.Frontiers in molecular neuroscience · 2022Review
- Sulfonium Ligands of the α7 nAChR.Molecules (Basel, Switzerland) · 2021Article
- Therapeutic Targeting ofPharmacological reviews · 2021Review
- The Positive Allosteric Modulation of alpha7-Nicotinic Cholinergic Receptors by GAT107 Increases Bacterial Lung Clearance in Hyperoxic Mice by Decreasing Oxidative Stress in Macrophages.Antioxidants (Basel, Switzerland) · 2021Article
- Design, synthesis, and electrophysiological evaluation of NS6740 derivatives: Exploration of the structure-activity relationship for alpha7 nicotinic acetylcholine receptor silent activation.European journal of medicinal chemistry · 2020Article
- Nicotinic acetylcholine receptors: Conventional and unconventional ligands and signaling.Neuropharmacology · 2020Review
- Impact of modulation of the α7 nicotinic acetylcholine receptor on nicotine reward in the mouse conditioned place preference test.Psychopharmacology · 2019Article
- Cracking the Betel Nut: Cholinergic Activity of Areca Alkaloids and Related Compounds.Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco · 2019Article
- Macroscopic and Microscopic Activation ofMolecular pharmacology · 2019Article
- Novel 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazoles to investigate the activation of the α7 nicotinic acetylcholine receptor subtype: Synthesis and electrophysiological evaluation.European journal of medicinal chemistry · 2018Article
- The Antinociceptive and Anti-Inflammatory Properties of theThe Journal of pharmacology and experimental therapeutics · 2018Article
- NS6740, an α7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity.Neuroscience letters · 2018Article
- Persistent activation of α7 nicotinic ACh receptors associated with stable induction of different desensitized states.British journal of pharmacology · 2018Article
Corrections and comments
- Erratum issued
Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The minimum pharmacophore for activation of the human α7 nicotinic acetylcholine receptor (nAChR) is the tetramethylammonium cation. Previous work demonstrated that larger quaternary ammonium compounds, such as diethyldimethylammonium or 1-methyl quinuclidine, were α7-selective partial agonists, but additional increase in the size of the ammonium cation or the quinuclidine N-alkyl group by a single carbon to an N-ethyl group led to a loss of efficacy for ion channel activation. We report that although such compounds are ineffective at inducing the normal channel open state, they nonetheless regulate the induction of specific conformational states normally considered downstream of channel activation. We synthesized several panels of quaternary ammonium nAChR ligands that systematically varied the size of the substituents bonded to the central positively charged nitrogen atom. In these molecular series, we found a correlation between the molecular volume of the ligand and/or charge density, and the receptor's preferred distribution among conformational states including the closed state, the active state, a nonconducting state that could be converted to an activated state by a positive allosteric modulator (PAM), and a PAM-insensitive nonconducting state. We hypothesize that the changes of molecular volume of an agonist's cationic core subtly impact interactions at the subunit interface constituting the orthosteric binding site in such a way as to regulate the probability of conversions among the conformational states. We define a new minimal pharmacophore for the class of compounds we have termed "silent agonists," which are able to induce allosteric modulator-dependent activation but not the normal activated state.
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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.