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

Cashin, Amanda L. and Petersson, E. James and Lester, Henry A. and Dougherty, Dennis A. (2005) Using Physical Chemistry To Differentiate Nicotinic from Cholinergic Agonists at the Nicotinic Acetylcholine Receptor. Journal of the American Chemical Society, 127 (1). pp. 350-356. ISSN 0002-7863. doi:10.1021/ja0461771. https://resolver.caltech.edu/CaltechAUTHORS:20170425-083958251

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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−π interaction with Trp α149, 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−π interaction and the backbone hydrogen bond. A simple structural model that considers only possible interactions with Trp α149 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ja0461771DOIArticle
http://pubs.acs.org/doi/abs/10.1021/ja0461771PublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/ja0461771PublisherSupporting Information
ORCID:
AuthorORCID
Petersson, E. James0000-0003-3854-9210
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2005 American Chemical Society. Received June 28, 2004. Publication Date (Web): December 2, 2004. We thank the NIH (NS 34407 and NS 11756) for support of this work, and Professor George Petersson for assistance.
Funders:
Funding AgencyGrant Number
NIHNS 34407
NIHNS 11756
Issue or Number:1
DOI:10.1021/ja0461771
Record Number:CaltechAUTHORS:20170425-083958251
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170425-083958251
Official Citation:Using Physical Chemistry To Differentiate Nicotinic from Cholinergic Agonists at the Nicotinic Acetylcholine Receptor Amanda L. Cashin, E. James Petersson, Henry A. Lester, and Dennis A. Dougherty Journal of the American Chemical Society 2005 127 (1), 350-356 DOI: 10.1021/ja0461771
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76902
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:25 Apr 2017 15:50
Last Modified:15 Nov 2021 17:03

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