• DOI:10.1124/jpet.104.078402
• Corpus ID: 15430117

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

@article{Fox2005PharmacologicalPO,
  title={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},
  author={Gerard B. Fox and Timothy A. Esbenshade and Jia Bao Pan and Richard J. Radek and Kathleen M. Krueger and Betty Bei Yao and Kaitlin E. Browman and Michael J. Buckley and Michael Edward Ballard and Victoria A. Komater and Holly M Miner and Min Zhang and Ramin Faghih and Lynne E. Rueter and Robert S. Bitner and Karla U. Drescher and Jill M. Wetter and Kennan Marsh and Martine Lemaire and Roger D. Porsolt and Youssef L. Bennani and James P. Sullivan and Marlon D. Cowart and Michael W. Decker and Arthur A. Hancock},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2005},
  volume={313},
  pages={176 - 190}
}

• G. Fox, T. Esbenshade, +22 authors A. Hancock
• Published 1 April 2005
• Biology, Chemistry
• Journal of Pharmacology and Experimental Therapeutics

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.