title: GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models.
abstract: 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) = 9.59 -9.90) and rat (pK(i) = 8.51-9.17) H(3) receptors. GSK189254 is >10,000-fold selective for human H(3) receptors versus other targets tested, and it exhibited potent functional antagonism (pA(2) = 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC(50) = 8.20 versus basal guanosine 5'-O-(3-[(35)S]thio)triphosphate binding] at the human recombinant H(3) receptor. In vitro autoradiography demonstrated specific [(3)H]GSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H(3) binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H(3) receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(-)-alpha-methyl[imidazole-2,5(n)-(3)H]histamine dihydrochloride ([(3)H]R-alpha-methylhistamine) binding (ED(50) = 0.17 mg/kg) and increased c-Fos immunoreactivity in prefrontal and somatosensory cortex (3 mg/kg). Microdialysis studies demonstrated that GSK189254 (0.3-3 mg/kg p.o.) increased the release of acetylcholine, noradrenaline, and dopamine in the anterior cingulate cortex and acetylcholine in the dorsal hippocampus. Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50) = 0.03 mg/kg p.o.). GSK189254 significantly improved performance of rats in diverse cognition paradigms, including passive avoidance (1 and 3 mg/kg p.o.), water maze (1 and 3 mg/kg p.o.), object recognition (0.3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders.
authors.affiliation: Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Third Ave., Harlow, Essex, CM19 5AW, UK. andy.medhurst@gsk.com
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Medhurst
authors.forename: Alan R
authors.initials: AR
authors.lastname: Atkins
authors.forename: Isabel J
authors.initials: IJ
authors.lastname: Beresford
authors.forename: Kim
authors.initials: K
authors.lastname: Brackenborough
authors.forename: Michael A
authors.initials: MA
authors.lastname: Briggs
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Calver
authors.forename: Jackie
authors.initials: J
authors.lastname: Cilia
authors.forename: Jane E
authors.initials: JE
authors.lastname: Cluderay
authors.forename: Barry
authors.initials: B
authors.lastname: Crook
authors.forename: John B
authors.initials: JB
authors.lastname: Davis
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Davis
authors.forename: Robert P
authors.initials: RP
authors.lastname: Davis
authors.forename: Lee A
authors.initials: LA
authors.lastname: Dawson
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Foley
authors.forename: Jane
authors.initials: J
authors.lastname: Gartlon
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Gonzalez
authors.forename: Teresa
authors.initials: T
authors.lastname: Heslop
authors.forename: Warren D
authors.initials: WD
authors.lastname: Hirst
authors.forename: Carol
authors.initials: C
authors.lastname: Jennings
authors.forename: Declan N C
authors.initials: DN
authors.lastname: Jones
authors.forename: Laurent P
authors.initials: LP
authors.lastname: Lacroix
authors.forename: Abbe
authors.initials: A
authors.lastname: Martyn
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ociepka
authors.forename: Alison
authors.initials: A
authors.lastname: Ray
authors.forename: Ciaran M
authors.initials: CM
authors.lastname: Regan
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Roberts
authors.forename: Joanne
authors.initials: J
authors.lastname: Schogger
authors.forename: Eric
authors.initials: E
authors.lastname: Southam
authors.forename: Tania O
authors.initials: TO
authors.lastname: Stean
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Trail
authors.forename: Neil
authors.initials: N
authors.lastname: Upton
authors.forename: Graham
authors.initials: G
authors.lastname: Wadsworth
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Wald
authors.forename: Trevor
authors.initials: T
authors.lastname: White
authors.forename: Jason
authors.initials: J
authors.lastname: Witherington
authors.forename: Marie L
authors.initials: ML
authors.lastname: Woolley
authors.forename: Angela
authors.initials: A
authors.lastname: Worby
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001552:Benzazepines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004285:Dogs; D017442:Histamine Agonists / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D006633:Histamine Antagonists / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D018697:Nootropic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000032:analysis / Q000378:metabolism*; D034421:Sus scrofa
chemical_list: D001552:Benzazepines; D017442:Histamine Agonists; D006633:Histamine Antagonists; D018377:Neurotransmitter Agents; D018697:Nootropic Agents; D018100:Receptors, Histamine H3; D009536:Niacinamide; C521312:6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide