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Research ArticleCellular and Molecular

Isoform Selectivity of Adenylyl Cyclase Inhibitors: Characterization of Known and Novel Compounds

Cameron S. Brand, Harrison J. Hocker, Alemayehu A. Gorfe, Claudio N. Cavasotto and Carmen W. Dessauer
Journal of Pharmacology and Experimental Therapeutics November 2013, 347 (2) 265-275; DOI: https://doi.org/10.1124/jpet.113.208157
Cameron S. Brand
Department of Integrative Biology and Pharmacology (C.S.B., H.J.H., A.A.G., C.W.D.), and School of Biomedical Informatics (C.N.C.), University of Texas Health Science Center, Houston, Texas; and Instituto de Investigación en Biomedicina de Buenos Aires-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina (C.N.C.)
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Harrison J. Hocker
Department of Integrative Biology and Pharmacology (C.S.B., H.J.H., A.A.G., C.W.D.), and School of Biomedical Informatics (C.N.C.), University of Texas Health Science Center, Houston, Texas; and Instituto de Investigación en Biomedicina de Buenos Aires-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina (C.N.C.)
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Alemayehu A. Gorfe
Department of Integrative Biology and Pharmacology (C.S.B., H.J.H., A.A.G., C.W.D.), and School of Biomedical Informatics (C.N.C.), University of Texas Health Science Center, Houston, Texas; and Instituto de Investigación en Biomedicina de Buenos Aires-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina (C.N.C.)
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Claudio N. Cavasotto
Department of Integrative Biology and Pharmacology (C.S.B., H.J.H., A.A.G., C.W.D.), and School of Biomedical Informatics (C.N.C.), University of Texas Health Science Center, Houston, Texas; and Instituto de Investigación en Biomedicina de Buenos Aires-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina (C.N.C.)
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Carmen W. Dessauer
Department of Integrative Biology and Pharmacology (C.S.B., H.J.H., A.A.G., C.W.D.), and School of Biomedical Informatics (C.N.C.), University of Texas Health Science Center, Houston, Texas; and Instituto de Investigación en Biomedicina de Buenos Aires-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina (C.N.C.)
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Abstract

Nine membrane-bound adenylyl cyclase (AC) isoforms catalyze the production of the second messenger cyclic AMP (cAMP) in response to various stimuli. Reduction of AC activity has well documented benefits, including benefits for heart disease and pain. These roles have inspired development of isoform-selective AC inhibitors, a lack of which currently limits exploration of functions and/or treatment of dysfunctions involving AC/cAMP signaling. However, inhibitors described as AC5- or AC1-selective have not been screened against the full panel of AC isoforms. We have measured pharmacological inhibitor profiles for all transmembrane AC isoforms. We found that 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22,536), 2-amino-7-(furanyl)-7,8-dihydro-5(6H)-quinazolinone (NKY80), and adenine 9-β-d-arabinofuranoside (Ara-A), described as supposedly AC5-selective, do not discriminate between AC5 and AC6, whereas the putative AC1-selective inhibitor 5-​[[2-​(6-​amino-​9H-​purin-​9-​yl)​ethyl]​amino]​-​1-​pentanol (NB001) does not directly target AC1 to reduce cAMP levels. A structure-based virtual screen targeting the ATP binding site of AC was used to identify novel chemical structures that show some preference for AC1 or AC2. Mutation of the AC2 forskolin binding pocket does not interfere with inhibition by SQ22,536 or the novel AC2 inhibitor, suggesting binding to the catalytic site. Thus, we show that compounds lacking the adenine chemical signature and targeting the ATP binding site can potentially be used to develop AC isoform–specific inhibitors, and discuss the need to reinterpret literature using AC5/6-selective molecules SQ22,536, NKY80, and Ara-A.

Footnotes

    • Received July 18, 2013.
    • Accepted September 3, 2013.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants GM60419 (to C.W.D.); R01GM10078 (to A.A.G.); and T32GM089657 (to C.S.B. and H.J.H.)]; the National Institutes of Health National Institute for Mental Health [Grant MH060397 (to C.W.D.)]; and the Agencia Nacional de Promoción Científica y Tecnológica, Argentina [Grant PICT-2011-2778 (to C.N.C.)].

  • Portions of this work were previously presented in abstract form: Brand CS, Hocker HJ, Gorfe AA, Cavasotto CN, and Dessauer CW (2013) Isoform selectivity of adenylyl cyclase inhibitors and identification of novel compounds. Experimental Biology; 2013 April 20–25, Boston, MA.

  • dx.doi.org/10.1124/jpet.113.208157.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 347 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 347, Issue 2
1 Nov 2013
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Research ArticleCellular and Molecular

Isoform Selectivity of Adenylyl Cyclase Inhibitors

Cameron S. Brand, Harrison J. Hocker, Alemayehu A. Gorfe, Claudio N. Cavasotto and Carmen W. Dessauer
Journal of Pharmacology and Experimental Therapeutics November 1, 2013, 347 (2) 265-275; DOI: https://doi.org/10.1124/jpet.113.208157

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Research ArticleCellular and Molecular

Isoform Selectivity of Adenylyl Cyclase Inhibitors

Cameron S. Brand, Harrison J. Hocker, Alemayehu A. Gorfe, Claudio N. Cavasotto and Carmen W. Dessauer
Journal of Pharmacology and Experimental Therapeutics November 1, 2013, 347 (2) 265-275; DOI: https://doi.org/10.1124/jpet.113.208157
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