title: Two novel and selective nonimidazole H3 receptor antagonists A-304121 and A-317920: II. In vivo behavioral and neurophysiological characterization.
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)-alpha-methylhistamine [(R)-alpha-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.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, AP9A, R4N5, 100 Abbott Park Road, Abbott Park, IL 60064-6115, USA. gerard.b.fox@abbott.com
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.forename: Jia Bao
authors.initials: JB
authors.lastname: Pan
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Radek
authors.forename: Angela M
authors.initials: AM
authors.lastname: Lewis
authors.forename: R Scott
authors.initials: RS
authors.lastname: Bitner
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.forename: Ramin
authors.initials: R
authors.lastname: Faghih
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
authors.forename: Michael
authors.initials: M
authors.lastname: Williams
authors.forename: Betty B
authors.initials: BB
authors.lastname: Yao
authors.forename: Michael W
authors.initials: MW
authors.lastname: Decker
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hancock
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D004569:Electroencephalography / Q000187:drug effects; D006633:Histamine Antagonists / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D018100:Receptors, Histamine H3 / Q000378:metabolism
chemical_list: C475225:4-((3-(4-(2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone; D006633:Histamine Antagonists; C475226:N-(2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide; D010879:Piperazines; D018100:Receptors, Histamine H3