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    Dualsteric Muscarinic Antagonists–Orthosteric Binding Pose Controls Allosteric Subtype Selectivity
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    † Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany
    ‡ Pharmacology and Toxicology, Institute of Pharmacy, Gerhard-Domagk-Straße 3,D-53121 Bonn, Germany
    § Institute for Pharmacy, Free University Berlin, Königin-Luise-Straße 2 und 4, D-14195 Berlin, Germany
    ∥ Institute of Pharmaceutical Biology, Molecular-, Cellular-, and Pharmacobiology Section, University of Bonn, Nussallee 6, D-53115 Bonn, Germany
    *For U.H. (medicinal chemistry): phone, +49-931-3185460; fax, +49-931-3185494; E-mail, [email protected]
    *For K.M. (pharmacology): phone, +49-228-739103; fax, +49-228-739215; E-mail, [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2014, 57, 15, 6739–6750
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    https://doi.org/10.1021/jm500790x
    Published July 22, 2014
    Copyright © 2014 American Chemical Society
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    Abstract

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    Bivalent ligands of G protein-coupled receptors have been shown to simultaneously either bind to two adjacent receptors or to bridge different parts of one receptor protein. Recently, we found that bivalent agonists of muscarinic receptors can simultaneously occupy both the orthosteric transmitter binding site and the allosteric vestibule of the receptor protein. Such dualsteric agonists display a certain extent of subtype selectivity, generate pathway-specific signaling, and in addition may allow for designed partial agonism. Here, we want to extend the concept to bivalent antagonism. Using the phthal- and naphthalimide moieties, which bind to the allosteric, extracellular site, and atropine or scopolamine as orthosteric building blocks, both connected by a hexamethonium linker, we were able to prove a bitopic binding mode of antagonist hybrids for the first time. This is demonstrated by structure–activity relationships, site-directed mutagenesis, molecular docking studies, and molecular dynamics simulations. Findings revealed that a difference in spatial orientation of the orthosteric tropane moiety translates into a divergent M2/M5 subtype selectivity of the corresponding bitopic hybrids.

    Copyright © 2014 American Chemical Society

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    Information about the molecular dynamics simulations. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cited By

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    This article is cited by 33 publications.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2014, 57, 15, 6739–6750
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm500790x
    Published July 22, 2014
    Copyright © 2014 American Chemical Society
    Request reuse permissions

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