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

@article{Fox2005PharmacologicalPO,
  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},
  author={Gerard B. Fox and Timothy A. Esbenshade and Jia Bao Pan and Richard J. Radek and Kathleen M. Krueger and Betty Bei Yao and Kaitlin E. Browman and Michael J. Buckley and Michael Edward Ballard and Victoria A. Komater and Holly M Miner and Min Zhang and Ramin Faghih and Lynne E. Rueter and Robert S. Bitner and Karla U. Drescher and Jill M. Wetter and Kennan Marsh and Martine Lemaire and Roger D. Porsolt and Youssef L. Bennani and James P. Sullivan and Marlon D. Cowart and Michael W. Decker and Arthur A. Hancock},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2005},
  volume={313},
  pages={176 - 190}
}
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… 
Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: I. Potent and Selective Histamine H3 Receptor Antagonist with Drug-Like Properties
TLDR
ABT-239 demonstrates good pharmacokinetic characteristics in rat, dog, and monkey with t1/2 values corresponding with clearance values and metabolic turnover in liver microsomes from these species, and good oral bioavailability ranging from 52 to 89%.
BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, Hydrochloride], a Nonimidazole Inverse Agonist/Antagonist at the Human Histamine H3 Receptor: Preclinical Pharmacology
TLDR
Preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.
Discovery and characterization of 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (CEP-26401, irdabisant): a potent, selective histamine H3 receptor inverse agonist.
TLDR
8a demonstrated ideal pharmaceutical properties for a CNS drug in regard to water solubility, permeability and lipophilicity and had low binding to human plasma proteins and it weakly inhibited recombinant cytochrome P450 isoforms and human ether-a-go- go-related gene.
Pharmacological properties and pro-cognitive effects of ABT-288, a potent and selective histamine H 3 receptor antagonist
TLDR
ABT-288 is a competitive antagonist with high affinity and selectivity for human and rat H 3 Rs that enhances the release of acetylcholine and dopamine in rat prefrontal cortex that attenuated methamphetamine-induced hyperactivity in mice.
Pharmacological Properties and Procognitive Effects of ABT-288, a Potent and Selective Histamine H3 Receptor Antagonist
TLDR
ABT-288 is a selective H3R antagonist with broad procognitive efficacy in rodents and excellent drug-like properties that support its advancement to the clinical area.
CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities
TLDR
The results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H3R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders.
A Novel Potent and Selective Histamine H3 Receptor Antagonist Enerisant: In Vitro Profiles, In Vivo Receptor Occupancy, and Wake-Promoting and Procognitive Effects in Rodents
TLDR
Enerisant is a novel histamine H3 receptor antagonist/inverse agonist that exerts wake-promoting and procognitive effects in addition to increasing the release of neurotransmitters related to these pharmacological effects in rodents.
GSK189254, a Novel H3 Receptor Antagonist That Binds to Histamine H3 Receptors in Alzheimer's Disease Brain and Improves Cognitive Performance in Preclinical Models
TLDR
Dense H3 binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H3 receptors are preserved in late-stage disease.
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References

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Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: I. Potent and Selective Histamine H3 Receptor Antagonist with Drug-Like Properties
TLDR
ABT-239 demonstrates good pharmacokinetic characteristics in rat, dog, and monkey with t1/2 values corresponding with clearance values and metabolic turnover in liver microsomes from these species, and good oral bioavailability ranging from 52 to 89%.
Two Novel and Selective Nonimidazole H3 Receptor Antagonists A-304121 and A-317920: II. In Vivo Behavioral and Neurophysiological Characterization
  • G. Fox, J. Pan, A. Hancock
  • Biology, Chemistry
    Journal of Pharmacology and Experimental Therapeutics
  • 2003
TLDR
A-304121 and A-317920 represent a series of novel, H3R-selective piperazine amides that enhance cognition in vivo, which could offer advantages over existing H3 R antagonists or cognition-enhancing agents.
ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride]: II. A novel cholinergic channel modulator with effects on cognitive performance in rats and monkeys.
TLDR
In rats and monkeys, acute administration of ABT-089 modestly improved the delayed matching-to-sample performance of mature, adult monkeys and more robustly improved performance in aged monkeys and was not accompanied by changes in response latencies.
Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist.
Differential in vivo effects of H3 receptor ligands in a new mouse dipsogenia model
Evaluation of the receptor selectivity of the H3 receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT3 receptor revealed
TLDR
The receptor selectivity of the potent histamine H3 receptor antagonist, iodophenpropit (IPP) in comparison with the prototype antagonist, thioperamide, was evaluated and IPP showed relatively high affinity for the 5‐hydroxytryptamine 5‐HT3 receptor.
Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist.
TLDR
Ciproxifan appears to be an orally bioavailable, extremely potent and selective H3-receptor antagonist whose vigilance- and attention-promoting effects are promising for therapeutic applications in aging disorders.
Characteristics of recombinantly expressed rat and human histamine H3 receptors.
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