2. Academic Validation
  3. GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models

GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models

  • J Pharmacol Exp Ther. 2007 Jun;321(3):1032-45. doi: 10.1124/jpet.107.120311.
Andrew D Medhurst 1,  Alan R Atkins,  Isabel J Beresford,  Kim Brackenborough,  Michael A Briggs,  Andrew R Calver,  Jackie Cilia,  Jane E Cluderay,  Barry Crook,  John B Davis,  Rebecca K Davis,  Robert P Davis,  Lee A Dawson,  Andrew G Foley,  Jane Gartlon,  M Isabel Gonzalez,  Teresa Heslop,  Warren D Hirst,  Carol Jennings,  Declan N C Jones,  Laurent P Lacroix,  Abbe Martyn,  Sandrine Ociepka,  Alison Ray,  Ciaran M Regan,  Jennifer C Roberts,  Joanne Schogger,  Eric Southam,  Tania O Stean,  Brenda K Trail,  Neil Upton,  Graham Wadsworth,  Jeffrey A Wald,  Trevor White,  Jason Witherington,  Marie L Woolley,  Angela Worby,  David M Wilson
Affiliations

Affiliation

  • 1 Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Third Ave., Harlow, Essex, CM19 5AW, UK. andy.medhurst@gsk.com
PMID: 17327487 DOI: 10.1124/jpet.107.120311
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.

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