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

  1. Andrew D. Medhurst,
  2. Alan R. Atkins,
  3. Isabel J. Beresford,
  4. Kim Brackenborough,
  5. Michael A. Briggs,
  6. Andrew R. Calver,
  7. Jackie Cilia,
  8. Jane E. Cluderay,
  9. Barry Crook,
  10. John B. Davis,
  11. Rebecca K. Davis,
  12. Robert P. Davis,
  13. Lee A. Dawson,
  14. Andrew G. Foley,
  15. Jane Gartlon,
  16. M. Isabel Gonzalez,
  17. Teresa Heslop,
  18. Warren D. Hirst,
  19. Carol Jennings,
  20. Declan N. C. Jones,
  21. Laurent P. Lacroix,
  22. Abbe Martyn,
  23. Sandrine Ociepka,
  24. Alison Ray,
  25. Ciaran M. Regan,
  26. Jennifer C. Roberts,
  27. Joanne Schogger,
  28. Eric Southam,
  29. Tania O. Stean,
  30. Brenda K. Trail,
  31. Neil Upton,
  32. Graham Wadsworth,
  33. Jeffrey A. Wald,
  34. Trevor White,
  35. Jason Witherington,
  36. Marie L. Woolley,
  37. Angela Worby and
  38. David M. Wilson
  1. 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.)
  1. 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

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 H3 receptor antagonist with high affinity for human (pKi = 9.59 –9.90) and rat (pKi = 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-(–)-α-methyl[imidazole-2,5(n)-3H]histamine dihydrochloride ([3H]R-α-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-α-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.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.120311.

  • ABBREVIATIONS: AD, Alzheimer's disease; H3, histamine H3; 5-HT, 5-hydroxytryptamine; MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); ABT-239, 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile; GSK189254, 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride; [3H]R-α-methylhistamine, R-(–)-α-methyl[imidazole-2,5(n)-3H]histamine dihydrochloride; HEK-293-MSR-II, human embryonic kidney-293-macrophage scavenger receptor class-II; HEK-293-Gαo, human embryonic kidney-293 cells stably expressing G protein Gαo; PBS, phosphate-buffered saline; GTPγS, guanosine 5′-O-(3-[35S]thio)triphosphate; CNS, central nervous system; HPLC, high-performance-liquid chromatography; IB, immunobuffer; T, trial period; SD, simple discrimination; CD, compound discrimination; REV, reversal learning; ID, intradimensional; ED, extradimensional; ANOVA, analysis of variance; ACh, acetylcholine; NSB, nonspecific binding; A-304121, 4-(3-((2R)-2-aminopropanoyl-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone; A-317920, N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-ox-ethyl-)-2-furamide; JNJ-5207852, 1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidine; SCH 79687, N-(3,5-dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea; NNC 38-1049, 1-cyclopentyl-4-(4-(4-chlorophenyl)-4-oxobutanoyl) piperazine.

    • Received January 22, 2007.
    • Accepted February 26, 2007.
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  1. Published online before print February 27, 2007, doi: 10.1124/jpet.107.120311 JPET June 2007 vol. 321 no. 3 1032-1045
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