title: SAR110894, a potent histamine H₃-receptor antagonist, displays procognitive effects in rodents.
abstract: SAR110894 is a novel histamine H₃-R ligand, displaying high and selective affinity for human, rat or mouse H₃-Rs. SAR110894 is a potent H₃-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H₃-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3-3 mg/kg, p.o.) or rats (0.3-1 mg/kg, p.o.). Moreover, SAR110894 (1 mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5 mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10 mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3 mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3-3 mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10 mg/kg, p.o.) or a parametric modification of the procedure (3 and 10 mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01-10 mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment β₂₅₋₃₅ in the object recognition test in mice (1 and 3 mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD.
authors.affiliation: Sanofi, Exploratory Unit, Chilly-Mazarin, France. guy.griebel@sanofi.com
authors.forename: Guy
authors.initials: G
authors.lastname: Griebel
authors.forename: Philippe
authors.initials: P
authors.lastname: Pichat
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Pruniaux
authors.forename: Sandra
authors.initials: S
authors.lastname: Beeské
authors.forename: Mati
authors.initials: M
authors.lastname: Lopez-Grancha
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Genet
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Terranova
authors.forename: Antonio
authors.initials: A
authors.lastname: Castro
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Sánchez
authors.forename: Mark
authors.initials: M
authors.lastname: Black
authors.forename: Geoffrey B
authors.initials: GB
authors.lastname: Varty
authors.forename: Ina
authors.initials: I
authors.lastname: Weiner
authors.forename: Michal
authors.initials: M
authors.lastname: Arad
authors.forename: Segev
authors.initials: S
authors.lastname: Barak
authors.forename: Amaya
authors.initials: A
authors.lastname: De Levie
authors.forename: Etienne
authors.initials: E
authors.lastname: Guillot
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects*; D005260:Female; D054828:Histamine H3 Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D018782:Maze Learning; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012559:Schizophrenia / Q000188:drug therapy
chemical_list: D054828:Histamine H3 Antagonists