TY - JOUR T1 - Pharmacological Properties and Procognitive Effects of ABT-288, a Potent and Selective Histamine H<sub>3</sub> Receptor Antagonist JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 233 LP - 245 DO - 10.1124/jpet.112.194126 VL - 343 IS - 1 AU - Timothy A. Esbenshade AU - Kaitlin E. Browman AU - Thomas R. Miller AU - Kathleen M. Krueger AU - Victoria Komater-Roderwald AU - Min Zhang AU - Gerard B. Fox AU - Lynne Rueter AU - Holly M. Robb AU - Richard J. Radek AU - Karla U. Drescher AU - Thomas A. Fey AU - R. Scott Bitner AU - Kennan Marsh AU - James S. Polakowski AU - Chen Zhao AU - Marlon D. Cowart AU - Arthur A. Hancock AU - James P. Sullivan AU - Jorge D. Brioni Y1 - 2012/10/01 UR - http://jpet.aspetjournals.org/content/343/1/233.abstract N2 - Blockade of the histamine H3 receptor (H3R) enhances central neurotransmitter release, making it an attractive target for the treatment of cognitive disorders. Here, we present in vitro and in vivo pharmacological profiles for the H3R antagonist 2-[4′-((3aR,6aR)-5-methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-biphenyl-4-yl]-2H-pyridazin-3-one (ABT-288). ABT-288 is a competitive antagonist with high affinity and selectivity for human and rat H3Rs (Ki = 1.9 and 8.2 nM, respectively) that enhances the release of acetylcholine and dopamine in rat prefrontal cortex. In rat behavioral tests, ABT-288 improved acquisition of a five-trial inhibitory avoidance test in rat pups (0.001–0.03 mg/kg), social recognition memory in adult rats (0.03–0.1 mg/kg), and spatial learning and reference memory in a rat water maze test (0.1–1.0 mg/kg). ABT-288 attenuated methamphetamine-induced hyperactivity in mice. In vivo rat brain H3R occupancy of ABT-288 was assessed in relation to rodent doses and exposure levels in behavioral tests. ABT-288 demonstrated a number of other favorable attributes, including good pharmacokinetics and oral bioavailability of 37 to 66%, with a wide central nervous system and cardiovascular safety margin. Thus, 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. ER -