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Research ArticleArticle

Distinct Profiles of α7 nAChR Positive Allosteric Modulation Revealed by Structurally Diverse Chemotypes

Jens Halvard Grønlien, Monika Håkerud, Hilde Ween, Kirsten Thorin-Hagene, Clark A. Briggs, Murali Gopalakrishnan and John Malysz
Molecular Pharmacology September 2007, 72 (3) 715-724; DOI: https://doi.org/10.1124/mol.107.035410
Jens Halvard Grønlien
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Monika Håkerud
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Hilde Ween
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Kirsten Thorin-Hagene
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Clark A. Briggs
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Murali Gopalakrishnan
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John Malysz
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Abstract

Selective modulation of α7 nicotinic acetylcholine receptors (nAChRs) is thought to regulate processes impaired in schizophrenia, Alzheimer's disease, and other dementias. One approach to target α7 nAChRs is by positive allosteric modulation. Structurally diverse compounds, including PNU-120596, 4-naphthalene-1-yl-3a,4,5,9b-tetrahydro-3-H-cyclopenta[c]quinoline-8-sulfonic acid amide (TQS), and 5-hydroxyindole (5-HI) have been identified as positive allosteric modulators (PAMs), but their receptor interactions and pharmacological profiles remain to be fully elucidated. In this study, we investigated interactions of these compounds at human α7 nAChRs, expressed in Xenopus laevis oocytes, along with genistein, a tyrosine kinase inhibitor. Genistein was found to function as a PAM. Two types of PAM profiles were observed. 5-HI and genistein predominantly affected the apparent peak current (type I) whereas PNU-120596 and TQS increased the apparent peak current and evoked a distinct weakly decaying current (type II). Concentration-responses to agonists [ACh, 3-[(3E)-3-[(2,4-dimethoxyphenyl)methylidene]-5,6-dihydro-4H-pyridin-2-yl]pyridine dihydrochloride (GTS-21), and N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-282987)] were potentiated by both types, although type II PAMs had greater effects. When applied after α7 nAChRs were desensitized, type II, but not type I, PAMs could reactivate α7 currents. Both types of PAMs also increased the ACh-evoked α7 window currents, with type II PAMs generally showing larger potentiation. None of the PAMs tested increased nicotine-evoked Ca2+ transients in human embryonic kidney 293 cells expressing human α4β2 or α3β4 nAChRs, although some inhibition was noted for 5-HI, genistein, and TQS. In summary, our studies reveal two distinct α7 PAM profiles, which could offer unique opportunities for modulating α7 nAChRs in vivo and in the development of novel therapeutics for central nervous system indications.

Footnotes

  • This work was supported by Abbott. All authors are employees of Abbott.

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

  • doi:10.1124/mol.107.035410.

  • ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; CNS, central nervous system; PNU-282987, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride; PAM, positive allosteric modulator; PNU-120596, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea; 5-HI, 5-hydroxyindole; TQS, 4-naphthalen-1-yl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonic acid amide; compound 6, N-(4-chlorophenyl)-α-[[(4-chloro-phenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide; MLA, methyllycaconitine; PP2, protein phosphatase 2; SU6656, 2-oxo-3-(4,5,6,7-tetrahydro-1H-indol-2-ylmethylene)-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide; FLIPR, fluorometric imaging plate reader; NMDG, N-methyl-d-glucamine; BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, acetoxymethyl ester; ARR17779, (5S)-spiro[1,3-oxazolidine-5,8′-1-azabicyclo[2.2.2]octane]-2-one.

    • Received February 21, 2007.
    • Accepted June 12, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (3)
Molecular Pharmacology
Vol. 72, Issue 3
1 Sep 2007
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Research ArticleArticle

Distinct Profiles of α7 nAChR Positive Allosteric Modulation Revealed by Structurally Diverse Chemotypes

Jens Halvard Grønlien, Monika Håkerud, Hilde Ween, Kirsten Thorin-Hagene, Clark A. Briggs, Murali Gopalakrishnan and John Malysz
Molecular Pharmacology September 1, 2007, 72 (3) 715-724; DOI: https://doi.org/10.1124/mol.107.035410

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Research ArticleArticle

Distinct Profiles of α7 nAChR Positive Allosteric Modulation Revealed by Structurally Diverse Chemotypes

Jens Halvard Grønlien, Monika Håkerud, Hilde Ween, Kirsten Thorin-Hagene, Clark A. Briggs, Murali Gopalakrishnan and John Malysz
Molecular Pharmacology September 1, 2007, 72 (3) 715-724; DOI: https://doi.org/10.1124/mol.107.035410
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