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L-733,060
Systematic (IUPAC) name
(2S,3S)-3-{[3,5-bis(trifluoromethyl)benzyl]oxy}-2-phenylpiperidine
Identifiers
CAS number 148700-85-0
ATC code  ?
PubChem 132846
Chemical data
Formula C 20H19F6NO 
Mol. mass 403.361 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes  ?

L-733,060 is a drug developed by Merck, Sharpe & Dohme which acts as an orally active, non-peptide, selective antagonist for the NK1 receptor, binding with a Ki of 0.08nM.[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 antiinflammatory 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

References

  1. ^ Seabrook GR, Shepheard SL, Williamson DJ, Tyrer P, Rigby M, Cascieri MA, Harrison T, Hargreaves RJ, Hill RG. L-733,060, a novel tachykinin NK1 receptor antagonist; effects in [Ca2+]i mobilisation, cardiovascular and dural extravasation assays. European Journal of Pharmacology. 1996 Dec 12;317(1):129-35. PMID 8982729
  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. Journal of Organic Chemistry. 2004 Sep 3;69(18):6001-9. PMID: 15373484
  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. Journal of Organic Chemistry. 2005 Mar 4;70(5):1780-5. PMID 15730301
  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. Journal of Organic Chemistry. 2008 Apr 18;73(8):3307-10. PMID 18331063
  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. 2003 Feb;14(1):87-95. PMID 12576885
  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. 2008 Jul;33(8):1919-28. PMID 17912250
  7. ^ Varty GB, Cohen-Williams ME, Morgan CA, Pylak U, Duffy RA, Lachowicz JE, Carey GJ, Coffin VL. The gerbil elevated plus-maze II: anxiolytic-like effects of selective neurokinin NK1 receptor antagonists. Neuropsychopharmacology. 2002 Sep;27(3):371-9. PMID 12225694
  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. 2001 Jun;937:121-31. PMID 11458533
  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. 2002 Jun;965:247-53. PMID 12105100
  10. ^ Noailles PA, Angulo JA. Neurokinin receptors modulate the neurochemical actions of cocaine. Annals of the New York Academy of Sciences. 2002 Jun;965:267-73. PMID 12105102
  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. 2002 Nov;83(3):613-22. PMID 12390523
  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. 2003 Jun 27;73(6):727-39. PMID 12801594
  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. Journal of Pharmacology and Experimental Therapeutics. 2003 Apr;305(1):31-9. PMID 12649350
  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. Journal of Pharmacology and Experimental Therapeutics. 2004 Mar;308(3):1174-80. PMID 14617692
  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. 2004 Apr 29;360(3):129-32. PMID 15082150
  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. 2007 Dec;107(6):1009-17. PMID 18043070
  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 and Visual Science. 2007 Jun;48(6):2775-81. PMID 17525212
  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. 2008 Apr;26(2):111-8. PMID 17906845
  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. 2008;29(4):245-54. PMID 18781096







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