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Research ArticleDrug Discovery and Translational Medicine

In Vitro Evaluation of Guanidine Analogs as Sigma Receptor Ligands for Potential Anti-Stroke Therapeutics

Adam A. Behensky, Michelle Cortes-Salva, Michael J. Seminerio, Rae R. Matsumoto, Jon C. Antilla and Javier Cuevas
Journal of Pharmacology and Experimental Therapeutics January 2013, 344 (1) 155-166; DOI: https://doi.org/10.1124/jpet.112.199513
Adam A. Behensky
Department of Molecular Pharmacology and Physiology, University of South Florida, College of Medicine (A.A.B., J.C.), and Department of Chemistry, University of South Florida, College of Arts and Sciences, Tampa, Florida (M.C.S., J.C.A.); and Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia (M.J.S., R.R.M.)
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Michelle Cortes-Salva
Department of Molecular Pharmacology and Physiology, University of South Florida, College of Medicine (A.A.B., J.C.), and Department of Chemistry, University of South Florida, College of Arts and Sciences, Tampa, Florida (M.C.S., J.C.A.); and Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia (M.J.S., R.R.M.)
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Michael J. Seminerio
Department of Molecular Pharmacology and Physiology, University of South Florida, College of Medicine (A.A.B., J.C.), and Department of Chemistry, University of South Florida, College of Arts and Sciences, Tampa, Florida (M.C.S., J.C.A.); and Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia (M.J.S., R.R.M.)
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Rae R. Matsumoto
Department of Molecular Pharmacology and Physiology, University of South Florida, College of Medicine (A.A.B., J.C.), and Department of Chemistry, University of South Florida, College of Arts and Sciences, Tampa, Florida (M.C.S., J.C.A.); and Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia (M.J.S., R.R.M.)
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Jon C. Antilla
Department of Molecular Pharmacology and Physiology, University of South Florida, College of Medicine (A.A.B., J.C.), and Department of Chemistry, University of South Florida, College of Arts and Sciences, Tampa, Florida (M.C.S., J.C.A.); and Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia (M.J.S., R.R.M.)
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Javier Cuevas
Department of Molecular Pharmacology and Physiology, University of South Florida, College of Medicine (A.A.B., J.C.), and Department of Chemistry, University of South Florida, College of Arts and Sciences, Tampa, Florida (M.C.S., J.C.A.); and Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia (M.J.S., R.R.M.)
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Abstract

Currently, the only Food and Drug Administration–approved treatment of acute stroke is recombinant tissue plasminogen activator, which must be administered within 6 hours after stroke onset. The pan-selective σ-receptor agonist N,N′-di-o-tolyl-guanidine (o-DTG) has been shown to reduce infarct volume in rats after middle cerebral artery occlusion, even when administered 24 hours after stroke. DTG derivatives were synthesized to develop novel compounds with greater potency than o-DTG. Fluorometric Ca2+ imaging was used in cultured cortical neurons to screen compounds for their capacity to reduce ischemia- and acidosis-evoked cytosolic Ca2+ overload, which has been linked to stroke-induced neurodegeneration. In both assays, migration of the methyl moiety produced no significant differences, but removal of the group increased potency of the compound for inhibiting acidosis-induced [Ca2+]i elevations. Chloro and bromo substitution of the methyl moiety in the meta and para positions increased potency by ≤160%, but fluoro substitutions had no effect. The most potent DTG derivative tested was N,N′-di-p-bromo-phenyl-guanidine (p-BrDPhG), which had an IC50 of 2.2 µM in the ischemia assay, compared with 74.7 μM for o-DTG. Microglial migration assays also showed that p-BrDPhG is more potent than o-DTG in this marker for microglial activation, which is also linked to neuronal injury after stroke. Radioligand binding studies showed that p-BrDPhG is a pan-selective σ ligand. Experiments using the σ-1 receptor-selective antagonist 1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride (BD-1063) demonstrated that p-BrDPhG blocks Ca2+ overload via σ-1 receptor activation. The study identified four compounds that may be more effective than o-DTG for the treatment of ischemic stroke at delayed time points.

Footnotes

  • This work was supported by the Florida Center of Excellence for Biomolecular Identification and Targeted Therapeutics [J.C., J.A.], the American Heart Association [Grant 11GRNT7990120 to J.C.], the State of Florida King Biomedical Research Program Team Science Program [J.C., J.A.], and the National Institutes of Health [Grants R01 DA013978 to R.M. and T32 GM081741 to M.S.].

  • dx.doi.org/10.1124/jpet.112.199513.

  • Received August 23, 2012.
  • Accepted October 11, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 1
1 Jan 2013
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Research ArticleDrug Discovery and Translational Medicine

Guanidine Analogs as Sigma Receptor Ligands

Adam A. Behensky, Michelle Cortes-Salva, Michael J. Seminerio, Rae R. Matsumoto, Jon C. Antilla and Javier Cuevas
Journal of Pharmacology and Experimental Therapeutics January 1, 2013, 344 (1) 155-166; DOI: https://doi.org/10.1124/jpet.112.199513

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Research ArticleDrug Discovery and Translational Medicine

Guanidine Analogs as Sigma Receptor Ligands

Adam A. Behensky, Michelle Cortes-Salva, Michael J. Seminerio, Rae R. Matsumoto, Jon C. Antilla and Javier Cuevas
Journal of Pharmacology and Experimental Therapeutics January 1, 2013, 344 (1) 155-166; DOI: https://doi.org/10.1124/jpet.112.199513
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