L-733,060

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L-733,060
L-733,060 structure.png
Systematic (IUPAC) name
(2S,3S)-3-{[3,5-bis(trifluoromethyl)benzyl]oxy}-2-phenylpiperidine
Clinical data
Legal status ?
Identifiers
CAS number 148700-85-0 YesY
ATC code ?
PubChem CID 132846
ChEMBL CHEMBL27006 N
Chemical data
Formula C20H19F6NO 
Mol. mass 403.361 g/mol
 N (what is this?)  (verify)

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[edit]

References[edit]

  1. ^ Seabrook, GR, Shepheard, SL, Williamson, DJ, Tyrer, P, Rigby, M, Cascieri, MA, Harrison, T, Hargreaves, RJ, Hill, RG (1996). "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. doi:10.1016/S0014-2999(96)00706-6. PMID 8982729. 
  2. ^ Liu, LX, Ruan, YP, Guo, ZQ, Huang, PQ (2004). "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. doi:10.1021/jo049166z. PMID 15373484. 
  3. ^ Tsai, MR, Chen, BF, Cheng, CC, Chang, NC (2005). "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. doi:10.1021/jo048073e. PMID 15730301. 
  4. ^ Liu, RH, Fang, K, Wang, B, Xu, MH, Lin, GQ (2008). "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. doi:10.1021/jo8002979. PMID 18331063. 
  5. ^ Varty, GB, Cohen-Williams, ME, Hunter, JC (2003). "The antidepressant-like effects of neurokinin NK1 receptor antagonists in a gerbil tail suspension test". Behavioural Pharmacology 14 (1): 87–95. doi:10.1097/01.fbp.0000055962.09493.e9 (inactive 2014-02-02). PMID 12576885. 
  6. ^ Wallace-Boone, TL, Newton, AE, Wright, RN, Lodge, NJ, McElroy, JF (2008). "Behavioral and pharmacological validation of the gerbil forced-swim test: effects of neurokinin-1 receptor antagonists". Neuropsychopharmacology 33 (8): 1919–28. doi:10.1038/sj.npp.1301586. PMID 17912250. 
  7. ^ Varty, GB, Cohen-Williams, ME, Morgan, CA, Pylak, U, Duffy, RA, Lachowicz, JE, Carey, GJ, Coffin, VL (2002). "The gerbil elevated plus-maze II: anxiolytic-like effects of selective neurokinin NK1 receptor antagonists". Neuropsychopharmacology 27 (3): 371–9. doi:10.1016/S0893-133X(02)00313-5. PMID 12225694. 
  8. ^ Kraft, M, Noailles, P, Angulo, JA (2001). "Substance P modulates cocaine-evoked dopamine overflow in the striatum of the rat brain". Annals of the New York Academy of Sciences 937: 121–31. PMID 11458533. 
  9. ^ Yu, J, Allison, S, Ibrahim, D, Cadet, JL, Angulo, JA (2002). "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: 247–53. PMID 12105100. 
  10. ^ Noailles, PA, Angulo, JA (2002). "Neurokinin receptors modulate the neurochemical actions of cocaine". Annals of the New York Academy of Sciences 965: 267–73. PMID 12105102. 
  11. ^ Yu, J, Cadet, JL, Angulo, JA (2002). "Neurokinin-1 (NK-1) receptor antagonists abrogate methamphetamine-induced striatal dopaminergic neurotoxicity in the murine brain". Journal of Neurochemistry 83 (3): 613–22. doi:10.1046/j.1471-4159.2002.01155.x. PMID 12390523. 
  12. ^ Loonam, TM, Noailles, PA, Yu, J, Zhu, JP, Angulo, JA (2003). "Substance P and cholecystokinin regulate neurochemical responses to cocaine and methamphetamine in the striatum". Life Sciences 73 (6): 727–39. doi:10.1016/S0024-3205(03)00393-X. PMID 12801594. 
  13. ^ Bang, R, Sass, G, Kiemer, AK, Vollmar, AM, Neuhuber, WL, Tiegs, G (2003). "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. doi:10.1124/jpet.102.043539. PMID 12649350. 
  14. ^ Bang, R, Biburger, M, Neuhuber, WL, Tiegs, G (2004). "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. doi:10.1124/jpet.103.059329. PMID 14617692. 
  15. ^ Jang, JH, Nam, TS, Paik, KS, Leem, JW (2004). "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. doi:10.1016/j.neulet.2004.02.043. PMID 15082150. 
  16. ^ Rittner, HL, Lux, C, Labuz, D, Mousa, SA, Schäfer, M, Stein, C, Brack, A (2007). "Neurokinin-1 receptor antagonists inhibit the recruitment of opioid-containing leukocytes and impair peripheral antinociception". Anesthesiology 107 (6): 1009–17. doi:10.1097/01.anes.0000291454.90754.de. PMID 18043070. 
  17. ^ Muñoz, M, Rosso, M, Coveñas, R, Montero, I, González-Moles, MA, Robles, MJ (2007). "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. doi:10.1167/iovs.05-1591. PMID 17525212. 
  18. ^ Muñoz, M, Rosso, M, Aguilar, FJ, González-Moles, MA, Redondo, M, Esteban, F (2008). "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. doi:10.1007/s10637-007-9087-y. PMID 17906845. 
  19. ^ Rosso, M, Robles-Frías, MJ, Coveñas, R, Salinas-Martín, MV, Muñoz, M (2008). "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 : the journal of the International Society for Oncodevelopmental Biology and Medicine 29 (4): 245–54. doi:10.1159/000152942. PMID 18781096.