L-733,060 Explained

L-733,060 is a drug developed by Merck which acts as an orally active, non-peptide, selective antagonist for the NK1 receptor, binding with a Ki of 0.08 nM.[1] Only one enantiomer is active which has made it the subject of several asymmetric synthesis efforts.[2] [3] [4]

L-733,060 has antidepressant[5] [6] and anxiolytic effects in animal studies,[7] and reduces both the dopamine release and neurotoxicity produced by methamphetamine and cocaine.[8] [9] [10] [11] [12] It shows anti-inflammatory and anti-hepatotoxic effects in animals,[13] [14] and counteracts the development of hyperalgesia following nerve injury.[15] [16] It also has anticancer effects in a variety of in vitro models.[17] [18] [19]

See also

Notes and References

  1. Seabrook GR, Shepheard SL, Williamson DJ, Tyrer P, Rigby M, Cascieri MA, Harrison T, Hargreaves RJ, Hill RG . 6 . L-733,060, a novel tachykinin NK1 receptor antagonist; effects in [Ca2+]i mobilisation, cardiovascular and dural extravasation assays . European Journal of Pharmacology . 317 . 1 . 129–35 . December 1996 . 8982729 . 10.1016/S0014-2999(96)00706-6 .
  2. Liu LX, Ruan YP, Guo ZQ, Huang PQ . A general approach to (5S,6R)-6-alkyl-5-benzyloxy-2-piperidinones: application to the asymmetric syntheses of neurokinin substance P receptor antagonist (-)-L-733,061 and (-)-deoxocassine . The Journal of Organic Chemistry . 69 . 18 . 6001–9 . September 2004 . 15373484 . 10.1021/jo049166z .
  3. Tsai MR, Chen BF, Cheng CC, Chang NC . A novel and highly regioselective approach to 5-methoxy-6-substituted-3-sulfonyl-delta-enlactams from 5-methoxy-3-sulfonyl glutarimide: synthesis of cis-2-substituted-3-piperidinols . The Journal of Organic Chemistry . 70 . 5 . 1780–5 . March 2005 . 15730301 . 10.1021/jo048073e .
  4. Liu RH, Fang K, Wang B, Xu MH, Lin GQ . Concise asymmetric synthesis of (+)-CP-99,994 and (+)-L-733,060 via efficient construction of homochiral syn-1,2-diamines and syn-1,2-amino alcohols . The Journal of Organic Chemistry . 73 . 8 . 3307–10 . April 2008 . 18331063 . 10.1021/jo8002979 .
  5. Varty GB, Cohen-Williams ME, Hunter JC . The antidepressant-like effects of neurokinin NK1 receptor antagonists in a gerbil tail suspension test . Behavioural Pharmacology . 14 . 1 . 87–95 . February 2003 . 12576885 . 10.1097/00008877-200302000-00009 . 12218489 .
  6. Wallace-Boone TL, Newton AE, Wright RN, Lodge NJ, McElroy JF . Behavioral and pharmacological validation of the gerbil forced-swim test: effects of neurokinin-1 receptor antagonists . Neuropsychopharmacology . 33 . 8 . 1919–28 . July 2008 . 17912250 . 10.1038/sj.npp.1301586 . free .
  7. Varty GB, Cohen-Williams ME, Morgan CA, Pylak U, Duffy RA, Lachowicz JE, Carey GJ, Coffin VL . 6 . The gerbil elevated plus-maze II: anxiolytic-like effects of selective neurokinin NK1 receptor antagonists . Neuropsychopharmacology . 27 . 3 . 371–9 . September 2002 . 12225694 . 10.1016/S0893-133X(02)00313-5 . free .
  8. Kraft M, Noailles P, Angulo JA . Substance P modulates cocaine-evoked dopamine overflow in the striatum of the rat brain . Annals of the New York Academy of Sciences . 937 . 1 . 121–31 . June 2001 . 11458533 . 10.1111/j.1749-6632.2001.tb03561.x . 2001NYASA.937..121K . 33530777 .
  9. Yu J, Allison S, Ibrahim D, Cadet JL, Angulo JA . Ontogeny of neurokinin-1 receptor mediation of methamphetamine neurotoxicity in the striatum of the mouse brain . Annals of the New York Academy of Sciences . 965 . 1 . 247–53 . June 2002 . 12105100 . 10.1111/j.1749-6632.2002.tb04166.x . 2002NYASA.965..247Y . 8945982 .
  10. Noailles PA, Angulo JA . Neurokinin receptors modulate the neurochemical actions of cocaine . Annals of the New York Academy of Sciences . 965 . 1 . 267–73 . June 2002 . 12105102 . 10.1111/j.1749-6632.2002.tb04168.x . 2002NYASA.965..267N . 35161445 .
  11. Yu J, Cadet JL, Angulo JA . Neurokinin-1 (NK-1) receptor antagonists abrogate methamphetamine-induced striatal dopaminergic neurotoxicity in the murine brain . Journal of Neurochemistry . 83 . 3 . 613–22 . November 2002 . 12390523 . 10.1046/j.1471-4159.2002.01155.x . free .
  12. Loonam TM, Noailles PA, Yu J, Zhu JP, Angulo JA . Substance P and cholecystokinin regulate neurochemical responses to cocaine and methamphetamine in the striatum . Life Sciences . 73 . 6 . 727–39 . June 2003 . 12801594 . 10.1016/S0024-3205(03)00393-X .
  13. Bang R, Sass G, Kiemer AK, Vollmar AM, Neuhuber WL, Tiegs G . Neurokinin-1 receptor antagonists CP-96,345 and L-733,060 protect mice from cytokine-mediated liver injury . The Journal of Pharmacology and Experimental Therapeutics . 305 . 1 . 31–9 . April 2003 . 12649350 . 10.1124/jpet.102.043539 . 10595836 .
  14. Bang R, Biburger M, Neuhuber WL, Tiegs G . Neurokinin-1 receptor antagonists protect mice from CD95- and tumor necrosis factor-alpha-mediated apoptotic liver damage . The Journal of Pharmacology and Experimental Therapeutics . 308 . 3 . 1174–80 . March 2004 . 14617692 . 10.1124/jpet.103.059329 . 11723933 .
  15. Jang JH, Nam TS, Paik KS, Leem JW . Involvement of peripherally released substance P and calcitonin gene-related peptide in mediating mechanical hyperalgesia in a traumatic neuropathy model of the rat . Neuroscience Letters . 360 . 3 . 129–32 . April 2004 . 15082150 . 10.1016/j.neulet.2004.02.043 . 11970289 .
  16. Rittner HL, Lux C, Labuz D, Mousa SA, Schäfer M, Stein C, Brack A . Neurokinin-1 receptor antagonists inhibit the recruitment of opioid-containing leukocytes and impair peripheral antinociception . Anesthesiology . 107 . 6 . 1009–17 . December 2007 . 18043070 . 10.1097/01.anes.0000291454.90754.de . free .
  17. Muñoz M, Rosso M, Coveñas R, Montero I, González-Moles MA, Robles MJ . Neurokinin-1 receptors located in human retinoblastoma cell lines: antitumor action of its antagonist, L-732,138 . Investigative Ophthalmology & Visual Science . 48 . 6 . 2775–81 . June 2007 . 17525212 . 10.1167/iovs.05-1591 . free .
  18. Muñoz M, Rosso M, Aguilar FJ, González-Moles MA, Redondo M, Esteban F . NK-1 receptor antagonists induce apoptosis and counteract substance P-related mitogenesis in human laryngeal cancer cell line HEp-2 . Investigational New Drugs . 26 . 2 . 111–8 . April 2008 . 17906845 . 10.1007/s10637-007-9087-y . 19157206 .
  19. Rosso M, Robles-Frías MJ, Coveñas R, Salinas-Martín MV, Muñoz M . The NK-1 receptor is expressed in human primary gastric and colon adenocarcinomas and is involved in the antitumor action of L-733,060 and the mitogenic action of substance P on human gastrointestinal cancer cell lines . Tumour Biology . 29 . 4 . 245–54 . 2008 . 18781096 . 10.1159/000152942 . 5177634 .

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