QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.107.120311v1 321/3/1032    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Medhurst, A. D. Articles by Wilson, D. M. Search for Related Content PubMed PubMed Citation Articles by Medhurst, A. D. Articles by Wilson, D. M.

NEUROPHARMACOLOGY

GSK189254, a Novel H₃ Receptor Antagonist That Binds to Histamine H₃ Receptors in Alzheimer's Disease Brain and Improves Cognitive Performance in Preclinical Models

Neurology and GI Centre of Excellence for Drug Discovery (A.D.M., K.B., M.A.B., A.R.C., B.C., J.B.D., R.K.D., R.P.D., M.I.G., T.H., W.D.H., S.O., A.R., J.C.R., J.S., T.O.S., B.K.T., N.U., G.W., T.W., J.W., D.M.W.), Psychiatry Centre of Excellence for Drug Discovery (A.R.A., J.C., J.E.C., L.A.D., J.G., C.J., D.N.C.J., L.P.L., A.M., E.S., M.L.W.), Global Project Management (I.J.B.), Discovery Research (A.W.), GlaxoSmithKline, Harlow, Essex, United Kingdom; Clinical Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina (J.A.W.); and Berand Limited, University College Dublin Conway Institute, University College Dublin, Belfield, Ireland (A.G.F., C.M.R.)

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H₃ receptor antagonist with high affinity for human (pK_i = 9.59 –9.90) and rat (pK_i = 8.51–9.17) H₃ receptors. GSK189254 is >10,000-fold selective for human H₃ receptors versus other targets tested, and it exhibited potent functional antagonism (pA₂ = 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC₅₀ = 8.20 versus basal guanosine 5'-O-(3-[³⁵S]thio)triphosphate binding] at the human recombinant H₃ receptor. In vitro autoradiography demonstrated specific [³H]GSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H₃ binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H₃ receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(–)--methyl[imidazole-2,5(n)-³H]histamine dihydrochloride ([³H]R--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 H₃ receptors was demonstrated by blockade of R--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.

Address correspondence to: Dr. Andrew D. Medhurst, Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Third Ave., Harlow, Essex, CM19 5AW, UK. E-mail. andy.medhurst{at}gsk.com

This article has been cited by other articles:

				S. Le, J. A. Gruner, J. R. Mathiasen, M. J. Marino, and H. Schaffhauser Correlation between ex Vivo Receptor Occupancy and Wake-Promoting Activity of Selective H3 Receptor Antagonists J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 902 - 909. [Abstract] [Full Text] [PDF]

				M. Hajos, C. J. Siok, W. E. Hoffmann, S. Li, and B. Kocsis Modulation of Hippocampal Theta Oscillation by Histamine H3 Receptors J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 391 - 398. [Abstract] [Full Text] [PDF]