(Redirected from SB-334,867)

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]

CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard100.164.490 Edit this at Wikidata
Chemical and physical data
Molar mass319.317 g/mol g·mol−1
3D model (JSmol)
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  1. ^ Smart, D; Sabido-David, C; Brough, SJ; Jewitt, F; Johns, A; Porter, RA; Jerman, JC (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; Upton, N; Porter, RA; Johns, A (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.
  3. ^ Haynes, AC; Chapman, H; Taylor, C; Moore, GB; Cawthorne, MA; Tadayyon, M; Clapham, JC; Arch, JR (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.
  4. ^ Rodgers, RJ; Ishii, Y; Halford, JC; Blundell, JE (2002). "Orexins and appetite regulation". Neuropeptides. 36 (5): 303–25. doi:10.1016/S0143-4179(02)00085-9. PMID 12450737.
  5. ^ Bernard, R; Lydic, R; Baghdoyan, HA (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. PMID 14622212.
  6. ^ Soffin, EM; Gill, CH; Brough, SJ; Jerman, JC; Davies, CH (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.
  7. ^ Thorpe, AJ; Kotz, CM (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.
  8. ^ Frederick-Duus, D; Guyton, MF; Fadel, J (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.
  9. ^ Small, CJ; Goubillon, ML; Murray, JF; Siddiqui, A; Grimshaw, SE; Young, H; Sivanesan, V; Kalamatianos, T; Kennedy, AR (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 (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 (2007). "A role for hypocretin (orexin) in male sexual behavior". Journal of Neuroscience. 27 (11): 2837–45. doi:10.1523/JNEUROSCI.4121-06.2007. PMID 17360905.
  12. ^ Eliassi, A; Nazari, M; Naghdi, N (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.
  13. ^ McElhinny, CJ; Lewin, AH; Mascarella, SW; Runyon, S; Brieaddy, L; Carroll, FI (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: 6661–6664. doi:10.1016/j.bmcl.2012.08.109.
  14. ^ Smart, D; Haynes, AC; Williams, G; Arch, JR (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 (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 (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; Sakurai, T; Yanagisawa, M; Nakamachi, T (2006). "Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine". Journal of Neuroscience. 26 (2): 398–405. doi:10.1523/JNEUROSCI.2761-05.2006. PMID 16407535.
  18. ^ Lawrence, AJ; Cowen, MS; Yang, HJ; Chen, F; Oldfield, B (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 (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; et al. (2014). "Blockade of hypocretin receptor-1 preferentially prevents cocaine seeking: comparison with natural reward seeking". NeuroReport. 25: 485–8. doi:10.1097/wnr.0000000000000120. PMC 3981907. PMID 24407199.