title: Pharmacological properties and procognitive effects of ABT-288, a potent and selective histamine H3 receptor antagonist.
abstract: Blockade of the histamine H(3) receptor (H(3)R) 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 H(3)R 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 H(3)Rs (K(i) = 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 H(3)R 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 H(3)R antagonist with broad procognitive efficacy in rodents and excellent drug-like properties that support its advancement to the clinical area.
authors: Global Pharmaceutical Research Division, Abbott Laboratories, Abbott Park, IL 60064, USA. Tim.Esbenshade@Abbott.com
authors: Timothy A
authors: TA
authors: Esbenshade
authors: Kaitlin E
authors: KE
authors: Browman
authors: Thomas R
authors: TR
authors: Miller
authors: Kathleen M
authors: KM
authors: Krueger
authors: Victoria
authors: V
authors: Komater-Roderwald
authors: Min
authors: M
authors: Zhang
authors: Gerard B
authors: GB
authors: Fox
authors: Lynne
authors: L
authors: Rueter
authors: Holly M
authors: HM
authors: Robb
authors: Richard J
authors: RJ
authors: Radek
authors: Karla U
authors: KU
authors: Drescher
authors: Thomas A
authors: TA
authors: Fey
authors: R Scott
authors: RS
authors: Bitner
authors: Kennan
authors: K
authors: Marsh
authors: James S
authors: JS
authors: Polakowski
authors: Chen
authors: C
authors: Zhao
authors: Marlon D
authors: MD
authors: Cowart
authors: Arthur A
authors: AA
authors: Hancock
authors: James P
authors: JP
authors: Sullivan
authors: Jorge D
authors: JD
authors: Brioni
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects* / Q000502:physiology*; D006168:Guinea Pigs; D057809:HEK293 Cells; D054828:Histamine H3 Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D018697:Nootropic Agents / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000502:physiology; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000502:physiology*; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology
chemical_list: C576396:2-(4'-(5-methylhexahydropyrrolo(3,4-b)pyrrol-1-yl)biphenyl-4-yl)-2H-pyridazin-3-one; D054828:Histamine H3 Antagonists; D018697:Nootropic Agents; D011724:Pyridazines; D011758:Pyrroles; D018100:Receptors, Histamine H3