RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 176
OP 190
DO 10.1124/jpet.104.078402
VO 313
IS 1
A1 Fox, Gerard B.
A1 Esbenshade, Timothy A.
A1 Pan, Jia Bao
A1 Radek, Richard J.
A1 Krueger, Kathleen M.
A1 Yao, Betty B.
A1 Browman, Kaitlin E.
A1 Buckley, Michael J.
A1 Ballard, Michael E.
A1 Komater, Victoria A.
A1 Miner, Holly
A1 Zhang, Min
A1 Faghih, Ramin
A1 Rueter, Lynne E.
A1 Bitner, R. Scott
A1 Drescher, Karla U.
A1 Wetter, Jill
A1 Marsh, Kennan
A1 Lemaire, Martine
A1 Porsolt, Roger D.
A1 Bennani, Youssef L.
A1 Sullivan, James P.
A1 Cowart, Marlon D.
A1 Decker, Michael W.
A1 Hancock, Arthur A.
YR 2005
UL http://jpet.aspetjournals.org/content/313/1/176.abstract
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