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Research ArticleNEUROPHARMACOLOGY

Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H3 Receptor Antagonist

Gerard B. Fox, Timothy A. Esbenshade, Jia Bao Pan, Richard J. Radek, Kathleen M. Krueger, Betty B. Yao, Kaitlin E. Browman, Michael J. Buckley, Michael E. Ballard, Victoria A. Komater, Holly Miner, Min Zhang, Ramin Faghih, Lynne E. Rueter, R. Scott Bitner, Karla U. Drescher, Jill Wetter, Kennan Marsh, Martine Lemaire, Roger D. Porsolt, Youssef L. Bennani, James P. Sullivan, Marlon D. Cowart, Michael W. Decker and Arthur A. Hancock
Journal of Pharmacology and Experimental Therapeutics April 2005, 313 (1) 176-190; DOI: https://doi.org/10.1124/jpet.104.078402
Gerard B. Fox
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Timothy A. Esbenshade
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Jia Bao Pan
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Richard J. Radek
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Kathleen M. Krueger
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Betty B. Yao
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Kaitlin E. Browman
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Michael J. Buckley
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Michael E. Ballard
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Victoria A. Komater
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Holly Miner
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Min Zhang
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Ramin Faghih
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Lynne E. Rueter
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R. Scott Bitner
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Karla U. Drescher
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Jill Wetter
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Kennan Marsh
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Abstract

Acute pharmacological blockade of central histamine H3 receptors (H3Rs) enhances arousal/attention in rodents. However, there is little information available for other behavioral domains or for repeated administration using selective compounds. ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] exemplifies such a selective, nonimidazole H3R antagonist with high affinity for rat (pKi = 8.9) and human (pKi = 9.5) H3Rs. Acute functional blockade of central H3 Rs was demonstrated by blocking the dipsogenia response to the selective H3R agonist (R)-α-methylhistamine in mice. In cognition studies, acquisition of a five-trial, inhibitory avoidance test in rat pups was improved with ABT-239 (0.1–1.0 mg/kg), a 10- to 150-fold gain in potency, with similar efficacy, over previous antagonists such as thioperamide, ciproxifan, A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl) methanone], A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl) phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide], and A-349821 [(4′-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone]. Efficacy in this model was maintained for 3 to 6 h and following repeated dosing with ABT-239. Social memory was also improved in adult (0.01–0.3 mg/kg) and aged (0.3–1.0 mg/kg) rats. In schizophrenia models, ABT-239 improved gating deficits in DBA/2 mice using prepulse inhibition of startle (1.0–3.0 mg/kg) and N40 (1.0–10.0 mg/kg). Furthermore, ABT-239 (1.0 mg/kg) attenuated methamphetamine-induced hyperactivity in mice. In freely moving rat microdialysis studies, ABT-239 enhanced acetylcholine release (0.1–3.0 mg/kg) in adult rat frontal cortex and hippocampus and enhanced dopamine release in frontal cortex (3.0 mg/kg), but not striatum. In summary, broad efficacy was observed with ABT-239 across animal models such that potential clinical efficacy may extend beyond disorders such as ADHD to include Alzheimer's disease and schizophrenia.

Footnotes

  • This work was supported by Abbott Laboratories.

  • Portions of this work were previously presented at the 32nd Annual European Histamine Research Society Meeting, Düsseldorf/Köln, Germany, April 28 to May 2, 2004, and at the 33rd Annual Society for Neuroscience Meeting, New Orleans, LA, November 8 to 12, 2003.

  • doi:10.1124/jpet.104.078402.

  • ABBREVIATIONS: ADHD, attention deficit hyperactivity disorder; AD, Alzheimer's disease; CNS, central nervous system; H3R, H3 receptor; A-304121, (4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone; A-317920, N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide; A-349821, (4′-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone; ABT-239, 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile; (R)-α-MeHA, (R)-α-methylhistamine; PPI, prepulse inhibition; SHR, spontaneously hypertensive rat; EEG, electroencephalogram; RID, ratio of investigation duration; ANOVA, analysis of variance; PLSD, protected least significant difference; MPH, methylphenidate; MAMPH, methamphetamine.

    • Received September 25, 2004.
    • Accepted December 13, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 381 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 381, Issue 2
1 May 2022
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Research ArticleNEUROPHARMACOLOGY

Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H3 Receptor Antagonist

Gerard B. Fox, Timothy A. Esbenshade, Jia Bao Pan, Richard J. Radek, Kathleen M. Krueger, Betty B. Yao, Kaitlin E. Browman, Michael J. Buckley, Michael E. Ballard, Victoria A. Komater, Holly Miner, Min Zhang, Ramin Faghih, Lynne E. Rueter, R. Scott Bitner, Karla U. Drescher, Jill Wetter, Kennan Marsh, Martine Lemaire, Roger D. Porsolt, Youssef L. Bennani, James P. Sullivan, Marlon D. Cowart, Michael W. Decker and Arthur A. Hancock
Journal of Pharmacology and Experimental Therapeutics April 1, 2005, 313 (1) 176-190; DOI: https://doi.org/10.1124/jpet.104.078402

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Research ArticleNEUROPHARMACOLOGY

Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H3 Receptor Antagonist

Gerard B. Fox, Timothy A. Esbenshade, Jia Bao Pan, Richard J. Radek, Kathleen M. Krueger, Betty B. Yao, Kaitlin E. Browman, Michael J. Buckley, Michael E. Ballard, Victoria A. Komater, Holly Miner, Min Zhang, Ramin Faghih, Lynne E. Rueter, R. Scott Bitner, Karla U. Drescher, Jill Wetter, Kennan Marsh, Martine Lemaire, Roger D. Porsolt, Youssef L. Bennani, James P. Sullivan, Marlon D. Cowart, Michael W. Decker and Arthur A. Hancock
Journal of Pharmacology and Experimental Therapeutics April 1, 2005, 313 (1) 176-190; DOI: https://doi.org/10.1124/jpet.104.078402
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