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GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models
- Source :
- The Journal of pharmacology and experimental therapeutics. 321(3)
- Publication Year :
- 2007
-
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.
- Subjects :
- Adult
Male
Niacinamide
Adolescent
medicine.drug_class
Sus scrofa
Histamine Antagonists
Pharmacology
Binding, Competitive
Histamine agonist
Cell Line
Histamine Agonists
Rats, Sprague-Dawley
chemistry.chemical_compound
Mice
Dogs
Alzheimer Disease
Ciproxifan
medicine
Animals
Humans
Receptors, Histamine H3
Rats, Wistar
Receptor
Maze Learning
Nootropic Agents
Aged
Temporal cortex
Aged, 80 and over
Neurotransmitter Agents
Chemistry
Brain
Benzazepines
Middle Aged
Receptor antagonist
Rats
Molecular Medicine
Histamine H3 receptor
H3 receptor antagonist
Acetylcholine
medicine.drug
Subjects
Details
- ISSN :
- 00223565
- Volume :
- 321
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Accession number :
- edsair.doi.dedup.....f2455dc58b48aabeec4028425d545f9f