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

Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH
Angela P. Bluma, Henry A. Lesterb, and Dennis A. Doughertya,1
+ Author Affiliations

aDivision of Chemistry and Chemical Engineering; and
bDivision of Biology, California Institute of Technology, Pasadena, CA 91125
Contributed by Dennis A. Dougherty, June 2, 2010 (sent for review April 1, 2010)

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.

Footnotes
1To whom correspondence should be addressed. E-mail: dadougherty@caltech.edu. 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.
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2009.
The authors declare no conflict of interest.
See Commentary on page 13195.
This article contains supporting information online at
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1007140107/-/DCSupplemental.

http://www.pnas.org/content/107/30/13206