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.
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.affiliation: Neuroscience Research, Global Pharmaceutical Research Division, Abbott Laboratories, AP9A, R4N5, Abbott Park, IL 60064-6115, USA. gerard.b.fox@abbott.com
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.forename: Jia Bao
authors.initials: JB
authors.lastname: Pan
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Radek
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Krueger
authors.forename: Betty B
authors.initials: BB
authors.lastname: Yao
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Browman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Buckley
authors.forename: Michael E
authors.initials: ME
authors.lastname: Ballard
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Komater
authors.forename: Holly
authors.initials: H
authors.lastname: Miner
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Ramin
authors.initials: R
authors.lastname: Faghih
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Rueter
authors.forename: R Scott
authors.initials: RS
authors.lastname: Bitner
authors.forename: Karla U
authors.initials: KU
authors.lastname: Drescher
authors.forename: Jill
authors.initials: J
authors.lastname: Wetter
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: Martine
authors.initials: M
authors.lastname: Lemaire
authors.forename: Roger D
authors.initials: RD
authors.lastname: Porsolt
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: Marlon D
authors.initials: MD
authors.lastname: Cowart
authors.forename: Michael W
authors.initials: MW
authors.lastname: Decker
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hancock
mesh_terms: D000375:Aging / Q000523:psychology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000697:Central Nervous System Stimulants; D003072:Cognition Disorders / Q000188:drug therapy* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004569:Electroencephalography / Q000187:drug effects; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D006948:Hyperkinesis / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008694:Methamphetamine; D051379:Mice; D008811:Mice, Inbred DBA; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy*; D012919:Social Behavior
chemical_list: D001572:Benzofurans; D000697:Central Nervous System Stimulants; D006633:Histamine Antagonists; D018377:Neurotransmitter Agents; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; D008694:Methamphetamine; C496397:benzonitrile, 4-(2-(2-((2r)-2-methyl-1-pyrrolidinyl)ethyl)-5-benzofuranyl)-