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Research ArticleArticle

Synthesis of Selective Agonists for the α7 Nicotinic Acetylcholine Receptor with In Situ Click-Chemistry on Acetylcholine-Binding Protein Templates

John G. Yamauchi, Kimberly Gomez, Neil Grimster, Mikael Dufouil, Ákos Nemecz, Joseph R. Fotsing, Kwok-Yiu Ho, Todd T. Talley, K. Barry Sharpless, Valery V. Fokin and Palmer Taylor
Molecular Pharmacology October 2012, 82 (4) 687-699; DOI: https://doi.org/10.1124/mol.112.080291
John G. Yamauchi
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences (J.G.Y., K.G., M.D., Á.N., K.H., T.T.T., P.T.), and Department of Chemistry and Biochemistry, Division of Physical Sciences (Á.N.), University of California, San Diego, La Jolla, California; and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (N.G., M.D., J.R.F., K.B.S., V.V.F.)
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Kimberly Gomez
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences (J.G.Y., K.G., M.D., Á.N., K.H., T.T.T., P.T.), and Department of Chemistry and Biochemistry, Division of Physical Sciences (Á.N.), University of California, San Diego, La Jolla, California; and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (N.G., M.D., J.R.F., K.B.S., V.V.F.)
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Neil Grimster
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences (J.G.Y., K.G., M.D., Á.N., K.H., T.T.T., P.T.), and Department of Chemistry and Biochemistry, Division of Physical Sciences (Á.N.), University of California, San Diego, La Jolla, California; and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (N.G., M.D., J.R.F., K.B.S., V.V.F.)
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Mikael Dufouil
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences (J.G.Y., K.G., M.D., Á.N., K.H., T.T.T., P.T.), and Department of Chemistry and Biochemistry, Division of Physical Sciences (Á.N.), University of California, San Diego, La Jolla, California; and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (N.G., M.D., J.R.F., K.B.S., V.V.F.)
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Ákos Nemecz
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences (J.G.Y., K.G., M.D., Á.N., K.H., T.T.T., P.T.), and Department of Chemistry and Biochemistry, Division of Physical Sciences (Á.N.), University of California, San Diego, La Jolla, California; and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (N.G., M.D., J.R.F., K.B.S., V.V.F.)
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Joseph R. Fotsing
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences (J.G.Y., K.G., M.D., Á.N., K.H., T.T.T., P.T.), and Department of Chemistry and Biochemistry, Division of Physical Sciences (Á.N.), University of California, San Diego, La Jolla, California; and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (N.G., M.D., J.R.F., K.B.S., V.V.F.)
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Kwok-Yiu Ho
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences (J.G.Y., K.G., M.D., Á.N., K.H., T.T.T., P.T.), and Department of Chemistry and Biochemistry, Division of Physical Sciences (Á.N.), University of California, San Diego, La Jolla, California; and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (N.G., M.D., J.R.F., K.B.S., V.V.F.)
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Todd T. Talley
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences (J.G.Y., K.G., M.D., Á.N., K.H., T.T.T., P.T.), and Department of Chemistry and Biochemistry, Division of Physical Sciences (Á.N.), University of California, San Diego, La Jolla, California; and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (N.G., M.D., J.R.F., K.B.S., V.V.F.)
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K. Barry Sharpless
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences (J.G.Y., K.G., M.D., Á.N., K.H., T.T.T., P.T.), and Department of Chemistry and Biochemistry, Division of Physical Sciences (Á.N.), University of California, San Diego, La Jolla, California; and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (N.G., M.D., J.R.F., K.B.S., V.V.F.)
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Valery V. Fokin
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences (J.G.Y., K.G., M.D., Á.N., K.H., T.T.T., P.T.), and Department of Chemistry and Biochemistry, Division of Physical Sciences (Á.N.), University of California, San Diego, La Jolla, California; and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (N.G., M.D., J.R.F., K.B.S., V.V.F.)
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Palmer Taylor
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences (J.G.Y., K.G., M.D., Á.N., K.H., T.T.T., P.T.), and Department of Chemistry and Biochemistry, Division of Physical Sciences (Á.N.), University of California, San Diego, La Jolla, California; and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (N.G., M.D., J.R.F., K.B.S., V.V.F.)
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Abstract

The acetylcholine-binding proteins (AChBPs), which serve as structural surrogates for the extracellular domain of nicotinic acetylcholine receptors (nAChRs), were used as reaction templates for in situ click-chemistry reactions to generate a congeneric series of triazoles from azide and alkyne building blocks. The catalysis of in situ azide-alkyne cycloaddition reactions at a dynamic subunit interface facilitated the synthesis of potentially selective compounds for nAChRs. We investigated compound sets generated in situ with soluble AChBP templates through pharmacological characterization with α7 and α4β2 nAChRs and 5-hydroxytryptamine type 3A receptors. Analysis of activity differences between the triazole 1,5-syn- and 1,4-anti-isomers showed a preference for the 1,4-anti-triazole regioisomers among nAChRs. To improve nAChR subtype selectivity, the highest-potency building block for α7 nAChRs, i.e., 3α-azido-N-methylammonium tropane, was used for additional in situ reactions with a mutated Aplysia californica AChBP that was made to resemble the ligand-binding domain of the α7 nAChR. Fourteen of 50 possible triazole products were identified, and their corresponding tertiary analogs were synthesized. Pharmacological assays revealed that the mutated binding protein template provided enhanced selectivity of ligands through in situ reactions. Discrete trends in pharmacological profiles were evident, with most compounds emerging as α7 nAChR agonists and α4β2 nAChR antagonists. Triazoles bearing quaternary tropanes and aromatic groups were most potent for α7 nAChRs. Pharmacological characterization of the in situ reaction products established that click-chemistry synthesis with surrogate receptor templates offered novel extensions of fragment-based drug design that were applicable to multisubunit ion channels.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants T32-GM07752, R01-GM18360-39, R01-GM087620]; the National Institutes of Health National Institute on Drug Abuse [Grant U01-DA019372]; and the National Science Foundation [Grant GK-12 0742551].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.080291.

  • ABBREVIATIONS:

    pLGIC
    pentameric, ligand-gated ion channel
    5-HT
    5-hydroxytrypamine
    AChBP
    acetylcholine-binding protein
    MT2
    mutant 2
    CNiFER
    cell-based neurotransmitter fluorescently engineered reporter
    CNS
    central nervous system
    CuAAC
    copper-catalyzed azide-alkyne cycloaddition
    DR
    dose ratio
    MLA
    methyllycaconitine
    nAChR
    nicotinic acetylcholine receptor
    TFA
    trifluoroacetic acid
    PDB
    Protein Data Bank
    HEK
    human embryonic kidney
    MS
    mass spectrometry
    LC
    liquid chromatography
    PNU-120596
    N-(5-chloro-2,4-dimethoxyphenyl)-N′-(5-methyl-3-isoxazolyl)urea.

  • Received May 28, 2012.
  • Accepted July 11, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (4)
Molecular Pharmacology
Vol. 82, Issue 4
1 Oct 2012
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Research ArticleArticle

nAChR Click-Chemistry Synthesis and Pharmacological Features

John G. Yamauchi, Kimberly Gomez, Neil Grimster, Mikael Dufouil, Ákos Nemecz, Joseph R. Fotsing, Kwok-Yiu Ho, Todd T. Talley, K. Barry Sharpless, Valery V. Fokin and Palmer Taylor
Molecular Pharmacology October 1, 2012, 82 (4) 687-699; DOI: https://doi.org/10.1124/mol.112.080291

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Research ArticleArticle

nAChR Click-Chemistry Synthesis and Pharmacological Features

John G. Yamauchi, Kimberly Gomez, Neil Grimster, Mikael Dufouil, Ákos Nemecz, Joseph R. Fotsing, Kwok-Yiu Ho, Todd T. Talley, K. Barry Sharpless, Valery V. Fokin and Palmer Taylor
Molecular Pharmacology October 1, 2012, 82 (4) 687-699; DOI: https://doi.org/10.1124/mol.112.080291
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