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

被引:269
作者
Medhurst, Andrew D.
Atkins, Alan R.
Beresford, Isabel J.
Brackenborough, Kim
Briggs, Michael A.
Calver, Andrew R.
Cilia, Jackie
Cluderay, Jane E.
Crook, Barry
Davis, John B.
Davis, Rebecca K.
Davis, Robert P.
Dawson, Lee A.
Foley, Andrew G.
Gartlon, Jane
Gonzalez, M. Isabel
Heslop, Teresa
Hirst, Warren D.
Jennings, Carol
Jones, Declan N. C.
Lacroix, Laurent P.
Martyn, Abbe
Ociepka, Sandrine
Ray, Alison
Regan, Ciaran M.
Roberts, Jennifer C.
Schogger, Joanne
Southam, Eric
Stean, Tania O.
Trail, Brenda K.
Upton, Neil
Wadsworth, Graham
Wald, Jeffrey A.
White, Trevor
Witherington, Jason
Woolley, Marie L.
Worby, Angela
Wilson, David M.
机构
[1] GlaxoSmithKline, Neurol & GI Ctr Excellence Drug Discovery, Harlow CM19 5AW, Essex, England
[2] GlaxoSmithKline, Psychiat Ctr Excellence Drug Discovery, Harlow CM19 5AW, Essex, England
[3] GlaxoSmithKline, Global Project Management, Harlow CM19 5AW, Essex, England
[4] GlaxoSmithKline, Discovery Res, Harlow CM19 5AW, Essex, England
[5] GlaxoSmithKline, Clin Pharmacokinet, Res Triangle Pk, NC USA
[6] Univ Coll Dublin, Conway Inst, Berand Ltd, Dublin 2, Ireland
关键词
D O I
10.1124/jpet.107.120311
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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-[S-35]thio)triphosphate binding] at the human recombinant H-3 receptor. In vitro autoradiography demonstrated specific [H-3]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)-H-3]histamine dihydrochloride ([H-3]R-alpha-methylhistamine) binding (ED50 = 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 (ID50 = 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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收藏
页码:1032 / 1045
页数:14
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