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Research ArticleArticle

A Series of α7 Nicotinic Acetylcholine Receptor Allosteric Modulators with Close Chemical Similarity but Diverse Pharmacological Properties

JasKiran K. Gill, Persis Dhankher, Tom D. Sheppard, Emanuele Sher and Neil S. Millar
Molecular Pharmacology May 2012, 81 (5) 710-718; DOI: https://doi.org/10.1124/mol.111.076026
JasKiran K. Gill
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Persis Dhankher
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Tom D. Sheppard
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Emanuele Sher
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Neil S. Millar
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Abstract

Acetylcholine activates nicotinic acetylcholine receptors (nAChRs) by binding to an extracellular site located at the interface of two adjacent subunits. In contrast, recent studies have provided evidence that positive allosteric modulators (PAMs) such as TQS (4-(naphthalen-2-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) and allosteric agonists such as 4BP-TQS (4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) interact at an intrasubunit transmembrane site. Here, we describe the synthesis and pharmacological characterization of a series of chemically related allosteric modulators of the α7 nAChR. Minimal changes in the chemical structure of these compounds have been found to exert profound effects on their pharmacological properties. For example, compounds containing a bromine atom at either the ortho or meta position on the phenyl ring, such as 2BP-TQS (4-(2-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) and 3BP-TQS (4-(3-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide), rather than at the para position (4BP-TQS), display no allosteric agonist activity but retain PAM activity on α7 nAChRs, demonstrating the importance of the location of the halogen atom on pharmacological properties. Replacement of the bromine atom in 4BP-TQS with either a chlorine [4CP-TQS (4-(4-chloroophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide)] or an iodine atom [4IP-TQS (4-(4-iodoophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide)] results in compounds that have pharmacological properties characteristic of allosteric agonists but display differences in activation rates, in inactivation rates, and in levels of desensitization. In contrast, replacement of the bromine atom in 4BP-TQS with a fluorine atom [4FP-TQS (4-(4-fluorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide)] generated a compound that lacks allosteric agonist activity but acts a potentiator of responses to acetylcholine. In addition, 4FP-TQS was found to act as an antagonist of responses evoked by allosteric agonists such as 4BP-TQS. These findings provide evidence of the pharmacological diversity of compounds interacting with the allosteric transmembrane site on α7 nAChRs.

Footnotes

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

  • This work was supported by the Biotechnology and Biological Sciences Research Council [Grant BB/F017146/1]; an Engineering and Physical Sciences Research Council Advanced Research Fellowship [Grant EP/E052789/1] (to T.S.); a Biotechnology and Biological Sciences Research Council (BBSRC) Collaborative Award in Science and Engineering Ph.D. studentship cofunded by BBSRC and Eli Lilly (to J.K.G.); and a Ph.D. studentship from the University College London Ph.D. program in drug discovery (P.D.).

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

    http://dx.doi.org/10.1124/mol.111.076026.

  • ABBREVIATIONS:

    nAChR
    nicotinic acetylcholine receptor
    2BP-TQS
    4-(2-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide
    2N-TQS
    4-(naphthalen-2-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide
    3,4BP-TQS
    4-(3,4-dibromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide
    3BP-TQS
    4-(3-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide
    3IP-TQS
    4-(3-iodophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide
    4BP-TQS
    4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide
    4CP-TQS
    4-(4-chloroophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide
    4FP-TQS
    4-(4-fluorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide
    4HP-TQS
    4-(4-hydroxyphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide
    4IP-TQS
    4-(4-iodoophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide
    4MP-TQS
    4-p-tolyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide
    4TF-TQS
    4-(4-(trifluoromethyl)phenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide
    ANOVA
    analysis of variance
    cRNA
    complementary RNA
    PAM
    positive allosteric modulator
    P-TQS
    4-phenyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide
    TQS
    4-(napthalen-1-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide.

  • Received January 16, 2012.
  • Accepted February 10, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (5)
Molecular Pharmacology
Vol. 81, Issue 5
1 May 2012
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Research ArticleArticle

Allosteric Modulation of the α7 Nicotinic Receptor

JasKiran K. Gill, Persis Dhankher, Tom D. Sheppard, Emanuele Sher and Neil S. Millar
Molecular Pharmacology May 1, 2012, 81 (5) 710-718; DOI: https://doi.org/10.1124/mol.111.076026

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Research ArticleArticle

Allosteric Modulation of the α7 Nicotinic Receptor

JasKiran K. Gill, Persis Dhankher, Tom D. Sheppard, Emanuele Sher and Neil S. Millar
Molecular Pharmacology May 1, 2012, 81 (5) 710-718; DOI: https://doi.org/10.1124/mol.111.076026
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