PT  - JOURNAL ARTICLE
AU  - Fox, Gerard B.
AU  - Esbenshade, Timothy A.
AU  - Pan, Jia Bao
AU  - Radek, Richard J.
AU  - Krueger, Kathleen M.
AU  - Yao, Betty B.
AU  - Browman, Kaitlin E.
AU  - Buckley, Michael J.
AU  - Ballard, Michael E.
AU  - Komater, Victoria A.
AU  - Miner, Holly
AU  - Zhang, Min
AU  - Faghih, Ramin
AU  - Rueter, Lynne E.
AU  - Bitner, R. Scott
AU  - Drescher, Karla U.
AU  - Wetter, Jill
AU  - Marsh, Kennan
AU  - Lemaire, Martine
AU  - Porsolt, Roger D.
AU  - Bennani, Youssef L.
AU  - Sullivan, James P.
AU  - Cowart, Marlon D.
AU  - Decker, Michael W.
AU  - Hancock, Arthur A.
TI  - Pharmacological Properties of ABT-239 [4-(2-{2-[(2<em>R</em>)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H<sub>3</sub> Receptor Antagonist
AID  - 10.1124/jpet.104.078402
DP  - 2005 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 176--190
VI  - 313
IP  - 1
4099  - http://jpet.aspetjournals.org/content/313/1/176.short
4100  - http://jpet.aspetjournals.org/content/313/1/176.full
SO  - J Pharmacol Exp Ther2005 Apr 01; 313
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics