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NEUROPHARMACOLOGY

Two Novel and Selective Nonimidazole H₃ Receptor Antagonists A-304121 and A-317920: II. In Vivo Behavioral and Neurophysiological Characterization

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois (G.B.F., J.B.P., R.J.R., A.M.L., R.S.B., T.A.E., R.F., B.B.Y., M.W.D., A.A.H.); Athersys, Cleveland, Ohio (Y.L.B.); and Northwestern University Medical School, Lake Forest, Illinois (M.W.)

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)--methylhistamine [(R)--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.

Address correspondence to: Dr. Gerard B. Fox, Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, AP9A, R4N5, 100 Abbott Park Road, Abbott Park, IL 60064-6115. E-mail: gerard.b.fox{at}abbott.com

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