Using Physical Chemistry To Differentiate Nicotinic from Cholinergic Agonists at the Nicotinic Acetylcholine Receptor
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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The EC50 for nicotine at (α4)2(β2)3 neuronal receptors is ~1 μM; at (α1)2β1γδ muscle receptors, ~400 μM.
“The EC50 for nicotine at (α4)2(β2)3 neuronal receptors is ~1 μM; at (α1)2β1γδ muscle receptors, ~ 400 μM.”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [46]
Nicotine makes neither the cation-π nor the hydrogen-bond interaction with the muscle receptor.
“Nicotine makes neither interaction with the muscle receptor (45,46).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [46]
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Nicotine binding to brain receptors requires a strong cation–π interaction
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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
- Publisher
- American Chemical Society (ACS)
- 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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