CI-988

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CI-988
(IUPAC) ime
4-([(1R)-2-([(2R)-3-(1H-indol-3-yl)-2-methyl-1-oxo-2-([(tricyclo[3.3.1.13,7]dec-2-yloxy) carbonyl]amino)propyl]amino)-1-phenylethyl]amino)-4-oxobutanoic acid
Klinički podaci
Identifikatori
CAS broj 130332-27-3
ATC kod ?
PubChem[1][2] 108186
Hemijski podaci
Formula C35H42N4O6 
Mol. masa 614.73 g/mol
SMILES eMolekuli & PubHem
Farmakoinformacioni podaci
Trudnoća ?
Pravni status

CI-988 (PD-134,308) je lek koji deluje kao holecistokininski antagonist, selektivan za CCKB tip. U životinjskim studijama on je manifestovao anksiolitsko dejstvo[3][4] kao i pojačanje analgetskog dejstva morfina[5] i endogenih opioidnih peptida,[6][7] sprečavanje razvoja tolerancije na opioide[8][9] i umanjenje simptoma povlačenja.[10][11] Konsekventno smatralo se da on možda može da nađe kliničku primenu u lečenju bola i anksioznosti kod ljudi, ali su rezultati kliničkih ispitivanja bili razočaravajući. Samo su minimalni terapeutski efekti primećeni čak i na visokim dozama.[12][13][14][15] Razlozi za neuspeh CI-988-a i drugih CCKB antagonista na ljudima uprkos pozitivnih rezultata na životinjama nisu jasni. Slabe farmakokinetičke osobine su moguće objašnjenje,[16] tako da se CCKB antagonisti još uvek istražuju kao mogući pomoćni lekovi za pojačanje dejstva drugih lekova.[17]

Reference[uredi | uredi kod]

  1. ↑ Li Q, Cheng T, Wang Y, Bryant SH (2010). „PubChem as a public resource for drug discovery.”. Drug Discov Today 15 (23-24): 1052-7. DOI:10.1016/j.drudis.2010.10.003. PMID 20970519.  edit
  2. ↑ Evan E. Bolton, Yanli Wang, Paul A. Thiessen, Stephen H. Bryant (2008). „Chapter 12 PubChem: Integrated Platform of Small Molecules and Biological Activities”. Annual Reports in Computational Chemistry 4: 217-241. DOI:10.1016/S1574-1400(08)00012-1. 
  3. ↑ Hughes J, Boden P, Costall B, Domeney A, Kelly E, Horwell DC, Hunter JC, Pinnock RD, Woodruff GN. Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity. Proceedings of the National Academy of Sciences USA. 1990 Sep;87(17):6728-32. PMID 1975695
  4. ↑ Singh L, Field MJ, Hughes J, Menzies R, Oles RJ, Vass CA, Woodruff GN. The behavioural properties of CI-988, a selective cholecystokininB receptor antagonist. British Journal of Pharmacology. 1991 Sep;104(1):239-45. PMID 1686205
  5. ↑ Wiesenfeld-Hallin Z, Xu XJ, Hughes J, Horwell DC, Hökfelt T. PD134308, a selective antagonist of cholecystokinin type B receptor, enhances the analgesic effect of morphine and synergistically interacts with intrathecal galanin to depress spinal nociceptive reflexes. Proceedings of the National Academy of Sciences USA. 1990 Sep;87(18):7105-9. PMID 1698290
  6. ↑ Durieux C, Derrien M, Maldonado R, Valverde O, Blommaert A, Fournié-Zaluski MC, Roques BP. CCK-B antagonists exhibit antidepressant-like effects and potentiate endogenous enkephalin analgesia. Correlation with in vivo binding affinities and brain penetration. Annals of the New York Academy of Sciences. 1994 Mar 23;713:355-7. PMID 8185186
  7. ↑ Valverde O, Maldonado R, Fournie-Zaluski MC, Roques BP. Cholecystokinin B antagonists strongly potentiate antinociception mediated by endogenous enkephalins. Journal of Pharmacology and Experimental Therapeutics. 1994 Jul;270(1):77-88. PMID 8035345
  8. ↑ Xu XJ, Wiesenfeld-Hallin Z, Hughes J, Horwell DC, Hökfelt T. CI988, a selective antagonist of cholecystokininB receptors, prevents morphine tolerance in the rat. British Journal of Pharmacology. 1992 Mar;105(3):591-6. PMID 1628146
  9. ↑ Hoffmann O, Wiesenfeld-Hallin Z. The CCK-B receptor antagonist Cl 988 reverses tolerance to morphine in rats. Neuroreport. 1994 Dec 20;5(18):2565-8. PMID 7696605
  10. ↑ Maldonado R, Valverde O, Ducos B, Blommaert AG, Fournie-Zaluski MC, Roques BP. Inhibition of morphine withdrawal by the association of RB 101, an inhibitor of enkephalin catabolism, and the CCKB antagonist PD-134,308. British Journal of Pharmacology. 1995 Mar;114(5):1031-9. PMID 7780637
  11. ↑ Valverde O, Roques BP. Cholecystokinin modulates the aversive component of morphine withdrawal syndrome in rats. Neuroscience Letters. 1998 Mar 6;244(1):37-40. PMID 9578139
  12. ↑ Bradwejn J, Koszycki D, Paradis M, Reece P, Hinton J, Sedman A. Effect of CI-988 on cholecystokinin tetrapeptide-induced panic symptoms in healthy volunteers. Biological Psychiatry. 1995 Dec 1;38(11):742-6. PMID 8580227
  13. ↑ Adams JB, Pyke RE, Costa J, Cutler NR, Schweizer E, Wilcox CS, Wisselink PG, Greiner M, Pierce MW, Pande AC. A double-blind, placebo-controlled study of a CCK-B receptor antagonist, CI-988, in patients with generalized anxiety disorder. Journal of Clinical Psychopharmacology. 1995 Dec;15(6):428-34. PMID 8748432
  14. ↑ van Megen HJ, Westenberg HG, den Boer JA, Slaap B, van Es-Radhakishun F, Pande AC. The cholecystokinin-B receptor antagonist CI-988 failed to affect CCK-4 induced symptoms in panic disorder patients. Psychopharmacology (Berlin). 1997 Feb;129(3):243-8. PMID 9084062
  15. ↑ Goddard AW, Woods SW, Money R, Pande AC, Charney DS, Goodman WK, Heninger GR, Price LH. Effects of the CCK(B) antagonist CI-988 on responses to mCPP in generalized anxiety disorder. Psychiatry Research. 1999 Mar 22;85(3):225-40. PMID 10333376
  16. ↑ Pande AC, Greiner M, Adams JB, Lydiard RB, Pierce MW. Placebo-controlled trial of the CCK-B antagonist, CI-988, in panic disorder. Biological Psychiatry. 1999 Sep 15;46(6):860-2. PMID 10494457
  17. ↑ Le Guen S, Mas Nieto M, Canestrelli C, Chen H, Fournié-Zaluski MC, Cupo A, Maldonado R, Roques BP, Noble F. Pain management by a new series of dual inhibitors of enkephalin degrading enzymes: long lasting antinociceptive properties and potentiation by CCK2 antagonist or methadone. Pain. 2003 Jul;104(1-2):139-48. DOI 10.1016/S0304-3959(02)00486-4 PMID 12855323

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