Abstract
Pharmacological blockade of central histamine H3 receptors (H3Rs) enhances cognition in rodents and offers promise for the clinical treatment of neurological disorders. However, many previously characterized H3R antagonists are either not selective for H3Rs or have potentially significant tolerability issues. Here, we present in vivo behavioral and neurophysiological data for two novel and selective H3R antagonists with improved safety indices. Functional blockade of central H3Rs was first demonstrated for A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone] (1 mg/kg) and A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl)-2-furamide] (0.45 mg/kg) by significantly attenuating an acute dipsogenia response to the selective H3R agonist (R)-α-methylhistamine [(R)-α-MeHA]. Cognitive performance was improved in a five-trial rat pup avoidance test following administration of A-304121 (10 mg/kg) or A-317920 (3 mg/kg), with efficacy comparable with previously published observations for reference H3R antagonists thioperamide (10 mg/kg), ciproxifan (3 mg/kg), and GT-2331 [(1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole] (1 mg/kg). Social memory was also significantly enhanced in the adult rat with A-304121 (3, 10 mg/kg) and A-317920 (1, 3 mg/kg) at doses that produced no significant change in electroencephalogram slow-wave amplitude activity. Relative therapeutic indices (TIs) of 30 and 42 were estimated for A-304121 and A-317920, respectively, by comparing doses producing adverse effects in general observation studies with potency in inhibitory avoidance, which were superior to TIs of 8, 10, and 18 observed for the reference antagonists thioperamide, ciproxifan, and GT-2331, respectively. 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 H3R antagonists or cognition-enhancing agents.
Footnotes
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Funded by Abbott Laboratories, Inc. Portions of this work were previously presented at the 31st Annual European Histamine Research Society Meeting, May 22–26, 2002 and at the 32nd Annual Society for Neuroscience Meeting, November 2–7, 2002.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.102.047241.
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ABBREVIATIONS: H3R, H3 receptor; (R)-α-MeHA, (R)-α-methylhistamine; A-304121, (4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy) phenyl)cyclopropylmethanone; A-317920, N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl)-2-furamide; ADHD, attention deficit hyperactivity disorder; GT-2331, (1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole; TIs, therapeutic indices; SHR, spontaneously hypertensive rat; RID, ratio of investigation duration; EEG, electroencephalogram; FFT, fast Fourier transform; ANOVA, analysis of variance; ABT-418, (S)-3-methyl-5(1-methyl-2-pyrrolidinyl)-isoxazole.
- Received November 26, 2002.
- Accepted February 14, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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