GSK-189254

GSK-189254
Identifiers
	IUPAC name 6-[(3-cyclobutyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)oxy]-N-methylpyridine-3-carboxamide;
CAS Number	720690-73-3;
PubChemCID	9798547;
ChemSpider	7974313;
UNII	5T4TX6CO53;
ChEMBL	ChEMBL517140;
CompTox Dashboard(EPA)	DTXSID801005982;
Chemical and physical data
Formula	C21H25N3O2
Molar mass	351.450g·mol−1
3D model (JSmol)	Interactive image;
	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); Key:WROHEWWOCPRMIA-UHFFFAOYSA-N;
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GSK-189,254is a potent and selectiveH₃histamine receptor inverse agonistdeveloped byGlaxoSmithKline.It has subnanomolar affinity for the H₃receptor (K_i= 0.2nM) and selectivity of over 10,000x for H₃over other histamine receptor subtypes.^[1]Animal studies have shown it to possess not onlystimulantandnootropiceffects,^[2]but alsoanalgesicaction suggesting a role for H₃receptors in pain processing in the spinal cord.^[3]GSK-189,254 and several other related drugs are currently being investigated as a treatment forAlzheimer's diseaseand other forms ofdementia,^[4]as well as possible use in the treatment of conditions such asnarcolepsy,^[5]orneuropathic painwhich do not respond well to conventional analgesic drugs.^[6]

References

^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.
^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.
^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.
^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.PMC2483387.PMID 18469850.
^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.PMC2697793.PMID 19413575.
^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.

[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.PMC2483387.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.PMC2697793.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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