GSK-189,254 is a potent and selective H3-receptorinverse 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. Animal studies have shown it to possess not only stimulant and nootropic effects, but also analgesic action suggesting a role for H3 receptors in pain processing in the spinal cord. GSK-189,254 and several other related drugs are currently being investigated as a treatment for Alzheimer's disease and other forms of dementia, as well as possible use in the treatment of conditions such as narcolepsy, or neuropathic pain which do not respond well to conventional analgesic drugs.
^Medhurst AD, Atkins AR, Beresford IJ, Brackenborough K, Briggs MA, Calver AR, Cilia J, Cluderay JE, Crook B, Davis JB, Davis RK, Davis RP, Dawson LA, Foley AG, Gartlon J, Gonzalez MI, Heslop T, Hirst WD, Jennings C, Jones DN, Lacroix LP, Martyn A, Ociepka S, Ray A, Regan CM, Roberts JC, Schogger J, Southam E, Stean TO, Trail BK, Upton N, Wadsworth G, Wald JA, White T, Witherington J, Woolley ML, Worby A, Wilson DM. GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models. Journal of Pharmacology and Experimental Therapeutics. 2007 Jun;321(3):1032-45. PMID 17327487
^Le S, Gruner JA, Mathiasen JR, Marino MJ, Schaffhauser H. Correlation between ex vivo receptor occupancy and wake-promoting activity of selective H3 receptor antagonists. Journal of Pharmacology and Experimental Therapeutics. 2008 Jun;325(3):902-9. doi:10.1124/jpet.107.135343PMID 18305012
^Medhurst SJ, Collins SD, Billinton A, Bingham S, Dalziel RG, Brass A, Roberts JC, Medhurst AD, Chessell IP. Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain. Pain. 2008 Aug 15;138(1):61-9. doi:10.1016/j.pain.2007.11.006PMID 18164820
^Guo RX, Anaclet C, Roberts JC, Parmentier R, Zhang M, Guidon G, Buda C, Sastre JP, Feng JQ, Franco P, Brown SH, Upton N, Medhurst AD, Lin JS. 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. 2009 May;157(1):104-17. PMID 19413575
^Medhurst AD, Briggs MA, Bruton G, Calver AR, Chessell I, Crook B, Davis JB, Davis RP, Foley AG, Heslop T, Hirst WD, Medhurst SJ, Ociepka S, Ray A, Regan CM, Sargent B, Schogger J, Stean TO, Trail BK, Upton N, White T, Orlek B, Wilson DM. Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats. Biochemical Pharmacology. 2007 Apr 15;73(8):1182-94. PMID 17276409