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Molecular Pharmacology

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Research ArticleArticle

Multiple Pharmacophores for the Selective Activation of Nicotinic α7-Type Acetylcholine Receptors

Nicole A. Horenstein, Fedra M. Leonik and Roger L. Papke
Molecular Pharmacology December 2008, 74 (6) 1496-1511; DOI: https://doi.org/10.1124/mol.108.048892
Nicole A. Horenstein
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Fedra M. Leonik
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Roger L. Papke
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Abstract

The activation of heteromeric and homomeric nicotinic acetylcholine receptors was studied in Xenopus laevis oocytes to identify key structures of putative agonist molecules associated with the selective activation of homomeric α7 receptors. We observed that selectivity between α7 and α4β2 was more readily obtained than selectivity between α7 and α3β4. Based on structural comparisons of previously characterized selective and nonselective agonists, we hypothesize at least three chemical motifs exist that, when present in molecules containing an appropriate cationic center, could be associated with the selective activation of α7 receptors. We identify the three distinct structural motifs based on prototypical drugs as the choline motif, the tropane motif, and the benzylidene motif. The choline motif involves the location of an oxygen-containing polar group such as a hydroxyl or carbonyl separated by two carbons from the charged nitrogen. The tropane motif provides α7-selectivity based on the addition of multiple small hydrophobic groups positioned away from the cationic center in specific orientations. We show that this motif can convert the nonselective agonists quinuclidine and ethyltrimethyl-ammonium to the α7-selective analogs methyl-quinuclidine and diethyldimethyl-ammonium, respectively. We have shown previously that the benzylidene group of 3-2,4, dimethoxy-benzylidene anabaseine (GTS-21) converts anabaseine into an α7-selective agonist. The benzylidene motif was also applied to quinuclidine to generate another distinct family of α7-selective agonists. Our results provide insight for the further development of nicotinic therapeutics and will be useful to direct future experiments with protein structure-based modeling and site-directed mutagenesis.

Footnotes

  • These studies were supported by National Institutes of Health grant GM57481.

  • ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; GTS-21, 3-2,4,dimethoxy-benzylidene anabaseine; TMA, tetramethyl-ammonium; ETMA, ethyltetramethyl-ammonium; dEdMA, diethyldimethylammonium; QN, quinuclidine; MQN, 1-methyl-1-azoniabicyclo[2.2.2]octane iodide; QN-O, quinuclidinone; QN-OH quinuclidinol; EQN, 1-ethyl-1-azoniabicyclo[2.2.2]octane iodide; BQNE, E-3-benzylidene-1-azoniabicyclo[2.2.2]-octane chloride; BQNZ, (Z)-3-benzylidene-1-azoniabicyclo[2.2.2]octane chloride; MBQNE, (E)-3-(4-methoxybenzylidene)-1-azoniabicyclo[2.2.2]-octane chloride; MBQNZ, (Z)-3-(4-methoxybenzylidene)-1-azoniabicyclo[2.2.2]octane chloride; DME, 1,2-dimethoxy ethane; ACME, cis-1-methyl-2,3,3a,4,5,9b,-hexahydro-1H-pyrrolo[2,3-f]quinoline; 5HT3, 5-hydroxytryptamine-3; ACh, acetylcholine; MS222, tricaine methanesulfonate.

    • Received May 16, 2008.
    • Accepted September 2, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (6)
Molecular Pharmacology
Vol. 74, Issue 6
1 Dec 2008
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Research ArticleArticle

Multiple Pharmacophores for the Selective Activation of Nicotinic α7-Type Acetylcholine Receptors

Nicole A. Horenstein, Fedra M. Leonik and Roger L. Papke
Molecular Pharmacology December 1, 2008, 74 (6) 1496-1511; DOI: https://doi.org/10.1124/mol.108.048892

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Research ArticleArticle

Multiple Pharmacophores for the Selective Activation of Nicotinic α7-Type Acetylcholine Receptors

Nicole A. Horenstein, Fedra M. Leonik and Roger L. Papke
Molecular Pharmacology December 1, 2008, 74 (6) 1496-1511; DOI: https://doi.org/10.1124/mol.108.048892
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