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Research ArticleDrug Discovery and Translational Medicine

NSC23766, a Widely Used Inhibitor of Rac1 Activation, Additionally Acts as a Competitive Antagonist at Muscarinic Acetylcholine Receptors

Magdolna Levay, Kurt Allen Krobert, Karola Wittig, Niels Voigt, Marcel Bermudez, Gerhard Wolber, Dobromir Dobrev, Finn Olav Levy and Thomas Wieland
Journal of Pharmacology and Experimental Therapeutics October 2013, 347 (1) 69-79; DOI: https://doi.org/10.1124/jpet.113.207266
Magdolna Levay
Institute of Experimental Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (M.L., K.W., T.W.); DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Mannheim, Germany (M.L., D.D., T.W.); Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine and K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway (K.A.K., F.O.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, and Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); and Computer-Aided Drug Design, Institute of Pharmacy, Free University of Berlin, Berlin, Germany (M.B., G.W.)
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Kurt Allen Krobert
Institute of Experimental Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (M.L., K.W., T.W.); DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Mannheim, Germany (M.L., D.D., T.W.); Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine and K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway (K.A.K., F.O.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, and Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); and Computer-Aided Drug Design, Institute of Pharmacy, Free University of Berlin, Berlin, Germany (M.B., G.W.)
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Karola Wittig
Institute of Experimental Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (M.L., K.W., T.W.); DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Mannheim, Germany (M.L., D.D., T.W.); Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine and K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway (K.A.K., F.O.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, and Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); and Computer-Aided Drug Design, Institute of Pharmacy, Free University of Berlin, Berlin, Germany (M.B., G.W.)
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Niels Voigt
Institute of Experimental Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (M.L., K.W., T.W.); DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Mannheim, Germany (M.L., D.D., T.W.); Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine and K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway (K.A.K., F.O.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, and Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); and Computer-Aided Drug Design, Institute of Pharmacy, Free University of Berlin, Berlin, Germany (M.B., G.W.)
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Marcel Bermudez
Institute of Experimental Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (M.L., K.W., T.W.); DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Mannheim, Germany (M.L., D.D., T.W.); Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine and K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway (K.A.K., F.O.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, and Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); and Computer-Aided Drug Design, Institute of Pharmacy, Free University of Berlin, Berlin, Germany (M.B., G.W.)
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Gerhard Wolber
Institute of Experimental Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (M.L., K.W., T.W.); DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Mannheim, Germany (M.L., D.D., T.W.); Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine and K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway (K.A.K., F.O.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, and Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); and Computer-Aided Drug Design, Institute of Pharmacy, Free University of Berlin, Berlin, Germany (M.B., G.W.)
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Dobromir Dobrev
Institute of Experimental Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (M.L., K.W., T.W.); DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Mannheim, Germany (M.L., D.D., T.W.); Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine and K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway (K.A.K., F.O.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, and Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); and Computer-Aided Drug Design, Institute of Pharmacy, Free University of Berlin, Berlin, Germany (M.B., G.W.)
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Finn Olav Levy
Institute of Experimental Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (M.L., K.W., T.W.); DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Mannheim, Germany (M.L., D.D., T.W.); Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine and K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway (K.A.K., F.O.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, and Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); and Computer-Aided Drug Design, Institute of Pharmacy, Free University of Berlin, Berlin, Germany (M.B., G.W.)
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Thomas Wieland
Institute of Experimental Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (M.L., K.W., T.W.); DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Mannheim, Germany (M.L., D.D., T.W.); Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine and K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway (K.A.K., F.O.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, and Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); and Computer-Aided Drug Design, Institute of Pharmacy, Free University of Berlin, Berlin, Germany (M.B., G.W.)
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Abstract

Small molecules interfering with Rac1 activation are considered as potential drugs and are already studied in animal models. A widely used inhibitor without reported attenuation of RhoA activity is NSC23766 [(N6-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride]. We found that NSC23766 inhibits the M2 muscarinic acetylcholine receptor (M2 mAChR)-induced Rac1 activation in neonatal rat cardiac myocytes. Surprisingly, NSC27366 concomitantly suppressed the carbachol-induced RhoA activation and a M2 mAChR-induced inotropic response in isolated neonatal rat hearts requiring the activation of Rho-dependent kinases. We therefore aimed to identify the mechanisms by which NSC23766 interferes with the differentially mediated, M2 mAChR-induced responses. Interestingly, NSC23766 caused a rightward shift of the carbachol concentration response curve for the positive inotropic response without modifying carbachol efficacy. To analyze the specificity of NSC23766, we compared the carbachol and the similarly Giβγ-mediated, adenosine-induced activation of Gi protein–regulated potassium channel (GIRK) channels in human atrial myocytes. Application of NSC23766 blocked the carbachol-induced K+ current but had no effect on the adenosine-induced GIRK current. Similarly, an adenosine A1 receptor-induced positive inotropic response in neonatal rat hearts was not attenuated by NSC23766. To investigate its specificity toward the different mAChR types, we studied the carbachol-induced elevation of intracellular Ca2+ concentrations in human embryonic kidney 293 (HEK-293) cells expressing M1, M2, or M3 mAChRs. NSC23766 caused a concentration-dependent rightward shift of the carbachol concentration response curves at all mAChRs. Thus, NSC23766 is not only an inhibitor of Rac1 activation, but it is within the same concentration range a competitive antagonist at mAChRs. Molecular docking analysis at M2 and M3 mAChR crystal structures confirmed this interpretation.

Footnotes

    • Received June 14, 2013.
    • Accepted July 22, 2013.
  • M.L. and K.A.K. contributed equally to this work.

  • The part of the study performed in Germany was supported by the DZHK (German Centre for Cardiovascular Research) and the BMBF (German Ministry of Education and Research). The work performed in Oslo was supported by the Norwegian Council on Cardiovascular Disease, the Research Council of Norway, Stiftelsen Kristian Gerhard Jebsen, South-Eastern Norway Regional Health Authority, Anders Jahre’s Foundation for the Promotion of Science, the Novo Nordisk Foundation, the Family Blix Foundation, the Simon Fougner Hartmann Family Foundation, and grants from the University of Oslo.

  • dx.doi.org/10.1124/jpet.113.207266.

  • ↵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 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 347, Issue 1
1 Oct 2013
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Research ArticleDrug Discovery and Translational Medicine

Competitive Antagonism of NSC23766 at mAChRs

Magdolna Levay, Kurt Allen Krobert, Karola Wittig, Niels Voigt, Marcel Bermudez, Gerhard Wolber, Dobromir Dobrev, Finn Olav Levy and Thomas Wieland
Journal of Pharmacology and Experimental Therapeutics October 1, 2013, 347 (1) 69-79; DOI: https://doi.org/10.1124/jpet.113.207266

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Research ArticleDrug Discovery and Translational Medicine

Competitive Antagonism of NSC23766 at mAChRs

Magdolna Levay, Kurt Allen Krobert, Karola Wittig, Niels Voigt, Marcel Bermudez, Gerhard Wolber, Dobromir Dobrev, Finn Olav Levy and Thomas Wieland
Journal of Pharmacology and Experimental Therapeutics October 1, 2013, 347 (1) 69-79; DOI: https://doi.org/10.1124/jpet.113.207266
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