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.

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 (pK(i) = 8.9) and human (pK(i) = 9.5) H3Rs. Acute functional blockade of central H3Rs 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.

• Authors: 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, Arthur A Hancock
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 313 Issue 1 Pg. 176-90 (Apr 2005) ISSN: 0022-3565 [Print] United States
• PMID: 15608077 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzofurans
• Central Nervous System Stimulants
• Histamine Antagonists
• Neurotransmitter Agents
• Pyrrolidines
• Receptors, Histamine H3
• Methamphetamine
• benzonitrile, 4-(2-(2-((2r)-2-methyl-1-pyrrolidinyl)ethyl)-5-benzofuranyl)-

Topics

• Aging (psychology)
• Animals
• Avoidance Learning (drug effects)
• Benzofurans (administration & dosage, pharmacology, therapeutic use)
• Central Nervous System Stimulants
• Cognition Disorders (drug therapy, psychology)
• Dose-Response Relationship, Drug
• Drinking (drug effects)
• Electroencephalography (drug effects)
• Histamine Antagonists (administration & dosage, pharmacology, therapeutic use)
• Hyperkinesis (chemically induced, prevention & control)
• Male
• Maze Learning (drug effects)
• Methamphetamine
• Mice
• Mice, Inbred DBA
• Microdialysis
• Neurons (drug effects, metabolism)
• Neurotransmitter Agents (metabolism)
• Pyrrolidines (administration & dosage, pharmacology, therapeutic use)
• Rats
• Rats, Inbred SHR
• Receptors, Histamine H3 (drug effects)
• Reflex, Startle (drug effects)
• Schizophrenia (drug therapy)
• Social Behavior