Cited by 120Nicotinic Acetylcholine Receptors StudyReceptor Mechanisms and SignalingNeuroscience and Neuropharmacology Research

Using Physical Chemistry To Differentiate Nicotinic from Cholinergic Agonists at the Nicotinic Acetylcholine Receptor

Cashin, Amanda L., Petersson, E. James, Lester, Henry A., Dougherty, Dennis A.·2005·Journal of the American Chemical Society

Abstract

The binding of three distinct agonists-acetylcholine (ACh), nicotine, and epibatidine-to the nicotinic acetylcholine receptor has been probed using unnatural amino acid mutagenesis. ACh makes a cation-pi interaction with Trp alpha149, while nicotine employs a hydrogen bond to a backbone carbonyl in the same region of the agonist binding site. The nicotine analogue epibatidine achieves its high potency by taking advantage of both the cation-pi interaction and the backbone hydrogen bond. A simple structural model that considers only possible interactions with Trp alpha149 suggests that a novel aromatic C-H...O=C hydrogen bond further augments the binding of epibatidine. These studies illustrate the subtleties and complexities of the interactions between drugs and membrane receptors and establish a paradigm for obtaining detailed structural information.

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Crossref · 10.1021/ja0461771

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Authors
Cashin, A. L., Petersson, E. J., Lester, H. A., & Dougherty, D. A.
Affiliations
California Institute of Technology (US)
Venue
Journal of the American Chemical Society
Published
2004-12-02
Volume
127
Issue
1
Pages
350-356
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
OpenAlex
W2033041174
Cited by
120
References
44
Citations by year
2025: 3 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 2 · 2014: 5 · 2013: 9 · 2012: 13
FWCI
4.03
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of the American Chemical Society (publishedVersion)
  • PubMed (publishedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
Funders
National Institute of Neurological Disorders and Stroke (NS34407, NS 11756, R01NS011756)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
nicotinic acetylcholine receptors, nicotinic agonists, cholinergic agonists, epibatidine, acetylcholine, nicotine, agonist binding site, cation-π interactions, hydrogen bonding, unnatural amino acid mutagenesis, ligand-receptor interactions
MeSH terms
Acetylcholine, Animals, Chemistry, Physical, Hydrogen Bonding, Kinetics, Models, Molecular, Nicotine, Pyridines, Receptors, Nicotinic, Surface Properties, Threonine, Tryptophan, Xenopus laevis, Crystallography, X-Ray, Cholinergic Agonists, Nicotinic Agonists, Bridged Bicyclo Compounds, Heterocyclic, Chemical Phenomena, Static Electricity

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