SB-334867

SB-334867 is an orexin antagonist. It was the first non-peptide antagonist developed that is selective for the orexin receptor subtype OX1, with around 50x selectivity for OX1 over OX2 receptors.[1] It has been shown to produce sedative and anorectic effects in animals,[2] and has been useful in characterising the orexinergic regulation of brain systems involved with appetite and sleep,[3][4][5][6][7][8] as well as other physiological processes.[9][10][11][12] The hydrochloride salt of SB-334867 has been demonstrated to be hydrolytically unstable, both in solution and as the solid.[13] Orexin antagonists have multiple potential clinical applications including the treatment of drug addiction, insomnia, obesity and diabetes.[14][15][16][17][18][19][20][21]

SB-334867
Identifiers
  • 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.164.490
Chemical and physical data
FormulaC17H13N5O2
Molar mass319.324 g·mol−1
3D model (JSmol)
  • O=C(Nc1c2ncccc2ncc1)Nc3ccc4nc(oc4c3)C
  • InChI=1S/C17H13N5O2/c1-10-20-12-5-4-11(9-15(12)24-10)21-17(23)22-14-6-8-18-13-3-2-7-19-16(13)14/h2-9H,1H3,(H2,18,21,22,23) checkY
  • Key:AKMNUCBQGHFICM-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

References
  1. Smart D, Sabido-David C, Brough SJ, Jewitt F, Johns A, Porter RA, Jerman JC (March 2001). "SB-334867-A: the first selective orexin-1 receptor antagonist". British Journal of Pharmacology. 132 (6): 1179–82. doi:10.1038/sj.bjp.0703953. PMC 1572677. PMID 11250867.
  2. Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, et al. (April 2001). "SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats". The European Journal of Neuroscience. 13 (7): 1444–52. doi:10.1046/j.0953-816x.2001.01518.x. PMID 11298806. S2CID 24935644.
  3. Haynes AC, Chapman H, Taylor C, Moore GB, Cawthorne MA, Tadayyon M, et al. (March 2002). "Anorectic, thermogenic and anti-obesity activity of a selective orexin-1 receptor antagonist in ob/ob mice". Regulatory Peptides. 104 (1–3): 153–9. doi:10.1016/S0167-0115(01)00358-5. PMID 11830290. S2CID 25523175.
  4. Rodgers RJ, Ishii Y, Halford JC, Blundell JE (October 2002). "Orexins and appetite regulation". Neuropeptides. 36 (5): 303–25. doi:10.1016/S0143-4179(02)00085-9. PMID 12450737. S2CID 23352886.
  5. Bernard R, Lydic R, Baghdoyan HA (October 2003). "Hypocretin-1 causes G protein activation and increases ACh release in rat pons" (PDF). The European Journal of Neuroscience. 18 (7): 1775–85. doi:10.1046/j.1460-9568.2003.02905.x. hdl:2027.42/75751. PMID 14622212. S2CID 18515164.
  6. Soffin EM, Gill CH, Brough SJ, Jerman JC, Davies CH (June 2004). "Pharmacological characterisation of the orexin receptor subtype mediating postsynaptic excitation in the rat dorsal raphe nucleus". Neuropharmacology. 46 (8): 1168–76. doi:10.1016/j.neuropharm.2004.02.014. PMID 15111023. S2CID 45872346.
  7. Thorpe AJ, Kotz CM (July 2005). "Orexin A in the nucleus accumbens stimulates feeding and locomotor activity". Brain Research. 1050 (1–2): 156–62. doi:10.1016/j.brainres.2005.05.045. PMID 15979595. S2CID 24662237.
  8. Frederick-Duus D, Guyton MF, Fadel J (November 2007). "Food-elicited increases in cortical acetylcholine release require orexin transmission". Neuroscience. 149 (3): 499–507. doi:10.1016/j.neuroscience.2007.07.061. PMID 17928158. S2CID 19452926.
  9. Small CJ, Goubillon ML, Murray JF, Siddiqui A, Grimshaw SE, Young H, et al. (July 2003). "Central orexin A has site-specific effects on luteinizing hormone release in female rats". Endocrinology. 144 (7): 3225–36. doi:10.1210/en.2002-0041. PMID 12810579.
  10. D'Anna KL, Gammie SC (August 2006). "Hypocretin-1 dose-dependently modulates maternal behaviour in mice". Journal of Neuroendocrinology. 18 (8): 553–66. doi:10.1111/j.1365-2826.2006.01448.x. PMC 2275401. PMID 16867176.
  11. Muschamp JW, Dominguez JM, Sato SM, Shen RY, Hull EM (March 2007). "A role for hypocretin (orexin) in male sexual behavior". The Journal of Neuroscience. 27 (11): 2837–45. doi:10.1523/JNEUROSCI.4121-06.2007. PMC 6672590. PMID 17360905.
  12. Eliassi A, Nazari M, Naghdi N (March 2009). "Role of the ventromedial hypothalamic orexin-1 receptors in regulation of gastric Acid secretion in conscious rats". Journal of Neuroendocrinology. 21 (3): 177–82. doi:10.1111/j.1365-2826.2009.01824.x. PMID 19207823. S2CID 23781282.
  13. McElhinny CJ, Lewin AH, Mascarella SW, Runyon S, Brieaddy L, Carroll FI (November 2012). "Hydrolytic instability of the important orexin 1 receptor antagonist SB-334867: possible confounding effects on in vivo and in vitro studies". Bioorganic & Medicinal Chemistry Letters. 22 (21): 6661–4. doi:10.1016/j.bmcl.2012.08.109. PMID 23031594.
  14. Smart D, Haynes AC, Williams G, Arch JR (April 2002). "Orexins and the treatment of obesity". European Journal of Pharmacology. 440 (2–3): 199–212. doi:10.1016/S0014-2999(02)01429-2. PMID 12007536.
  15. Bingham MJ, Cai J, Deehan MR (September 2006). "Eating, sleeping and rewarding: orexin receptors and their antagonists". Current Opinion in Drug Discovery & Development. 9 (5): 551–9. PMID 17002215.
  16. Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A (February 2006). "Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine". Neuron. 49 (4): 589–601. doi:10.1016/j.neuron.2006.01.016. PMID 16476667.
  17. Narita M, Nagumo Y, Hashimoto S, Narita M, Khotib J, Miyatake M, et al. (January 2006). "Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine". The Journal of Neuroscience. 26 (2): 398–405. doi:10.1523/JNEUROSCI.2761-05.2006. PMC 6674410. PMID 16407535.
  18. Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B (July 2006). "The orexin system regulates alcohol-seeking in rats". British Journal of Pharmacology. 148 (6): 752–9. doi:10.1038/sj.bjp.0706789. PMC 1617074. PMID 16751790.
  19. Sharf R, Sarhan M, Dileone RJ (August 2008). "Orexin mediates the expression of precipitated morphine withdrawal and concurrent activation of the nucleus accumbens shell". Biological Psychiatry. 64 (3): 175–83. doi:10.1016/j.biopsych.2008.03.006. PMC 2529153. PMID 18423425.
  20. Aston-Jones G, Smith RJ, Moorman DE, Richardson KA (2009). "Role of lateral hypothalamic orexin neurons in reward processing and addiction". Neuropharmacology. 56 Suppl 1 (Suppl 1): 112–21. doi:10.1016/j.neuropharm.2008.06.060. PMC 2635332. PMID 18655797.
  21. Martin-Fardon R, Weiss F (May 2014). "Blockade of hypocretin receptor-1 preferentially prevents cocaine seeking: comparison with natural reward seeking". NeuroReport. 25 (7): 485–8. doi:10.1097/wnr.0000000000000120. PMC 3981907. PMID 24407199.
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