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

被引:225
作者
Fox, GB
Esbenshade, TA
Pan, JB
Radek, RJ
Krueger, KM
Yao, BB
Browman, KE
Buckley, MJ
Ballard, ME
Komater, VA
Miner, H
Zhang, M
Faghih, R
Rueter, LE
Bitner, RS
Drescher, KU
Wetter, J
Marsh, K
Lemaire, M
Porsolt, RD
Bennani, YL
机构
[1] Abbott Labs, Global Pharmaceut Res Div, Neurosci Res, Abbott Pk, IL 60064 USA
[2] Abbott GmbH & Co, Global Pharmaceut Res Div, Neurosci Res, Ludwigshafen, Germany
[3] Porsolt & Partners Pharmacol, Boulogne, France
[4] Vertex Pharmaceut, Cambridge, MA USA
关键词
D O I
10.1124/jpet.104.078402
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Acute pharmacological blockade of central histamine H-3 receptors (H(3)Rs) 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 (pK(i) = 8.9) and human (pK(i) = 9.5) H(3)Rs. Acute functional blockade of central H(3)Rs was demonstrated by blocking the dipsogenia response to the selective H3R agonist (R)-alpha-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.
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收藏
页码:176 / 190
页数:15
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