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Molecular Pharmacology

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Research ArticleArticle

A Novel Multivalent Ligand That Bridges the Allosteric and Orthosteric Binding Sites of the M2 Muscarinic Receptor

Tod Steinfeld, Mathai Mammen, Jacqueline A. M. Smith, Richard D. Wilson and Jeffrey R. Jasper
Molecular Pharmacology August 2007, 72 (2) 291-302; DOI: https://doi.org/10.1124/mol.106.033746
Tod Steinfeld
Theravance, Inc., South San Francisco, California
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Mathai Mammen
Theravance, Inc., South San Francisco, California
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Jacqueline A. M. Smith
Theravance, Inc., South San Francisco, California
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Richard D. Wilson
Theravance, Inc., South San Francisco, California
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Jeffrey R. Jasper
Theravance, Inc., South San Francisco, California
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Abstract

THRX-160209 is a potent antagonist at the M2 muscarinic acetylcholine (ACh) receptor subtype that was designed using a multivalent strategy, simultaneously targeting the orthosteric site and a nearby site known to bind allosteric ligands. In this report, we describe three characteristics of THRX-160209 binding that are consistent with a multivalent interaction: 1) an apparent affinity of the multivalent ligand for the M2 receptor subtype (apparent pKI = 9.51 ± 0.22) that was several orders of magnitude greater than its two monovalent components (apparent pKI values < 6.0), 2) specificity of THRX-160209 for the M2 receptor subtype compared with the closely related M4 (apparent pKI = 8.78 ± 0.24) and M1,M3, and M5 receptors (apparent pKI values ≤ 8.0), and 3) acceleration (>10-fold) of the dissociation rate of tritium-labeled THRX-160209 from M2 receptors by competing monovalent ligands that are known to interact with either the orthosteric site (e.g., atropine) or a well characterized allosteric site (e.g., obidoxime) on the receptor. In complementary kinetic studies assessing allosteric modulation of the receptor, unlabeled THRX-160209 retarded dissociation of [3H]N-methyl scopolamine (NMS). The effects of THRX-160209 on retardation of [3H]NMS dissociation were competitively inhibited by obidoxime, suggesting that obidoxime and THRX-160209 bind to an overlapping region coincident with other typical muscarinic allosteric agents, such as 3-methyl-5-[7-[4-[(4S)-4-methyl-1,3-oxazolidin-2-yl]phenoxy]heptyl]-1,2-oxazole (W84) and gallamine. Taken together, these data are consistent with the hypothesis that THRX-160209 binds in a multivalent manner to the M2 receptor, simultaneously occupying the orthosteric site and a spatially distinct allosteric site.

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Molecular Pharmacology: 72 (2)
Molecular Pharmacology
Vol. 72, Issue 2
1 Aug 2007
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Research ArticleArticle

A Novel Multivalent Ligand That Bridges the Allosteric and Orthosteric Binding Sites of the M2 Muscarinic Receptor

Tod Steinfeld, Mathai Mammen, Jacqueline A. M. Smith, Richard D. Wilson and Jeffrey R. Jasper
Molecular Pharmacology August 1, 2007, 72 (2) 291-302; DOI: https://doi.org/10.1124/mol.106.033746

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Research ArticleArticle

A Novel Multivalent Ligand That Bridges the Allosteric and Orthosteric Binding Sites of the M2 Muscarinic Receptor

Tod Steinfeld, Mathai Mammen, Jacqueline A. M. Smith, Richard D. Wilson and Jeffrey R. Jasper
Molecular Pharmacology August 1, 2007, 72 (2) 291-302; DOI: https://doi.org/10.1124/mol.106.033746
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