GSK-189254

GSK-189,254 is a potent and selective H3 histamine receptor inverse agonist developed by GlaxoSmithKline. It has subnanomolar affinity for the H3 receptor (Ki = 0.2nM) and selectivity of over 10,000x for H3 over other histamine receptor subtypes.[1] Animal studies have shown it to possess not only stimulant and nootropic effects,[2] but also analgesic action suggesting a role for H3 receptors in pain processing in the spinal cord.[3] GSK-189,254 and several other related drugs are currently being investigated as a treatment for Alzheimer's disease and other forms of dementia,[4] as well as possible use in the treatment of conditions such as narcolepsy,[5] or neuropathic pain which do not respond well to conventional analgesic drugs.[6]

GSK-189254
Identifiers
IUPAC name
  • 6-[(3-cyclobutyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)oxy]-N-methylpyridine-3-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H25N3O2
Molar mass351.450 g·mol−1
3D model (JSmol)
SMILES
  • c4cc1CCN(C3CCC3)CCc1cc4Oc(cc2)ncc2C(=O)NC
InChI
  • InChI=1S/C21H25N3O2/c1-22-21(25)17-6-8-20(23-14-17)26-19-7-5-15-9-11-24(18-3-2-4-18)12-10-16(15)13-19/h5-8,13-14,18H,2-4,9-12H2,1H3,(H,22,25) N
  • Key:WROHEWWOCPRMIA-UHFFFAOYSA-N N
 NY (what is this?)  (verify)

References
  1. Medhurst AD, Atkins AR, Beresford IJ, Brackenborough K, Briggs MA, Calver AR, et al. (June 2007). "GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models". The Journal of Pharmacology and Experimental Therapeutics. 321 (3): 1032–45. doi:10.1124/jpet.107.120311. PMID 17327487. S2CID 14312511.
  2. Le S, Gruner JA, Mathiasen JR, Marino MJ, Schaffhauser H (June 2008). "Correlation between ex vivo receptor occupancy and wake-promoting activity of selective H3 receptor antagonists". The Journal of Pharmacology and Experimental Therapeutics. 325 (3): 902–9. doi:10.1124/jpet.107.135343. PMID 18305012. S2CID 26536000.
  3. Medhurst SJ, Collins SD, Billinton A, Bingham S, Dalziel RG, Brass A, et al. (August 2008). "Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain". Pain. 138 (1): 61–9. doi:10.1016/j.pain.2007.11.006. PMID 18164820. S2CID 43724064.
  4. Esbenshade TA, Browman KE, Bitner RS, Strakhova M, Cowart MD, Brioni JD (July 2008). "The histamine H3 receptor: an attractive target for the treatment of cognitive disorders". British Journal of Pharmacology. 154 (6): 1166–81. doi:10.1038/bjp.2008.147. PMC 2483387. PMID 18469850.
  5. Guo RX, Anaclet C, Roberts JC, Parmentier R, Zhang M, Guidon G, et al. (May 2009). "Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep-wake cycle and narcoleptic episodes in Ox-/- mice". British Journal of Pharmacology. 157 (1): 104–17. doi:10.1111/j.1476-5381.2009.00205.x. PMC 2697793. PMID 19413575.
  6. Medhurst AD, Briggs MA, Bruton G, Calver AR, Chessell I, Crook B, et al. (April 2007). "Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats". Biochemical Pharmacology. 73 (8): 1182–94. doi:10.1016/j.bcp.2007.01.007. PMID 17276409.
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