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Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH

Blum, Angela P. and Lester, Henry A. and Dougherty, Dennis A. (2010) Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH. Proceedings of the National Academy of Sciences of the United States of America, 107 (30). pp. 13206-13211. ISSN 0027-8424. PMCID PMC2922130. doi:10.1073/pnas.1007140107. https://resolver.caltech.edu/CaltechAUTHORS:20100913-091409908

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Abstract

Pharmacophore models for nicotinic agonists have been proposed for four decades. Central to these models is the presence of a cationic nitrogen and a hydrogen bond acceptor. It is now well-established that the cationic center makes an important cation-π interaction to a conserved tryptophan, but the donor to the proposed hydrogen bond acceptor has been more challenging to identify. A structure of nicotine bound to the acetylcholine binding protein predicted that the binding partner of the pharmacophore’s second component was a water molecule, which also hydrogen bonds to the backbone of the complementary subunit of the receptors. Here we use unnatural amino acid mutagenesis coupled with agonist analogs to examine whether such a hydrogen bond is functionally significant in the α4β2 neuronal nAChR, the receptor most associated with nicotine addiction. We find evidence for the hydrogen bond with the agonists nicotine, acetylcholine, carbamylcholine, and epibatidine. These data represent a completed nicotinic pharmacophore and offer insight into the design of new therapeutic agents that selectively target these receptors.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1007140107 DOIArticle
http://www.pnas.org/content/107/30/13206.abstractPublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922130/PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2010 by the National Academy of Sciences. This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2009. Contributed by Dennis A. Dougherty, June 2, 2010 (sent for review April 1, 2010). Published online before print June 28, 2010. We thank Ariele P. Hanek and Sean M. A. Kedrowski for helpful discussions. This work was supported by the National Institutes of Health (NS 34407; NS 11756) and the California Tobacco-Related Disease Research Program of the University of California, Grant 16RT-0160. Author contributions: A.P.B. and D.A.D. designed research; A.P.B. performed research; A.P.B., H.A.L., and D.A.D. analyzed data; and A.P.B., H.A.L., and D.A.D. wrote the paper.
Funders:
Funding AgencyGrant Number
NIHNS 34407
NIHNS 11756
California Tobacco-Related Disease Research Program of the University of California16RT-0160
Issue or Number:30
PubMed Central ID:PMC2922130
DOI:10.1073/pnas.1007140107
Record Number:CaltechAUTHORS:20100913-091409908
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20100913-091409908
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:19886
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:16 Sep 2010 21:17
Last Modified:08 Nov 2021 23:55

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