CI-988

С Википедије, слободне енциклопедије
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
Identifikatori
CAS broj130332-27-3 ДаY
PubChemCID 108186
Hemijski podaci
FormulaC35H42N4O6
Molarna masa614.73 g/mol
  • CC(CC1=CNC2=CC=CC=C21)(C(=O)NCC(C3=CC=CC=C3)NC(=O)CCC(=O)O)NC(=O)OC4C5CC6CC(C5)CC4C6.CNCC(C(C(C(CO)O)O)O)O

CI-988 (PD-134,308) je lek koji deluje kao holecistokininski antagonist, selektivan za CCKB tip. U životinjskim studijama on je manifestovao anksiolitsko dejstvo[1][2] kao i pojačanje analgetskog dejstva morfina[3] i endogenih opioidnih peptida,[4][5] sprečavanje razvoja tolerancije na opioide[6][7] i umanjenje simptoma povlačenja.[8][9] 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.[10][11][12][13] 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,[14] tako da se CCKB antagonisti još uvek istražuju kao mogući pomoćni lekovi za pojačanje dejstva drugih lekova.[15]

Reference[уреди | уреди извор]

  1. ^ Hughes, J.; Boden, P.; Costall, B.; Domeney, A.; Kelly, E.; Horwell, D. C.; Hunter, J. C.; Pinnock, R. D.; Woodruff, G. N. (1990). „Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity”. Proceedings of the National Academy of Sciences of the United States of America. 1975695 (17): 6728—6732. Bibcode:1990PNAS...87.6728H. PMC 54610Слободан приступ. PMID 1975695. doi:10.1073/pnas.87.17.6728Слободан приступ. 
  2. ^ Singh, L.; Field, M. J.; Hughes, J.; Menzies, R.; Oles, R. J.; Vass, C. A.; Woodruff, G. N. (1991). „The behavioural properties of CI-988, a selective cholecystokininB receptor antagonist”. British Journal of Pharmacology. 1686205 (1): 239—245. PMC 1908271Слободан приступ. PMID 1686205. doi:10.1111/j.1476-5381.1991.tb12413.x. 
  3. ^ Wiesenfeld-Hallin, Z.; Xu, X. J.; Hughes, J.; Horwell, D. C.; Hökfelt, T. (1990). „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 of the United States of America. 1698290 (18): 7105—7109. Bibcode:1990PNAS...87.7105W. PMC 54692Слободан приступ. PMID 1698290. doi:10.1073/pnas.87.18.7105Слободан приступ. 
  4. ^ Durieux, C.; Derrien, M.; Maldonado, R.; Valverde, O.; Blommaert, A.; Fournié-Zaluski, M. C.; Roques, B. P. (1994). „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. 8185186: 355—357. PMID 8185186. S2CID 23317834. doi:10.1111/j.1749-6632.1994.tb44091.x. 
  5. ^ Valverde, O.; Maldonado, R.; Fournie-Zaluski, M. C.; Roques, B. P. (1994). „Cholecystokinin B antagonists strongly potentiate antinociception mediated by endogenous enkephalins”. The Journal of Pharmacology and Experimental Therapeutics. 8035345 (1): 77—88. PMID 8035345. 
  6. ^ Xu, X. J.; Wiesenfeld-Hallin, Z.; Hughes, J.; Horwell, D. C.; Hökfelt, T. (1992). „CI988, a selective antagonist of cholecystokininB receptors, prevents morphine tolerance in the rat”. British Journal of Pharmacology. 1628146 (3): 591—596. PMC 1908430Слободан приступ. PMID 1628146. doi:10.1111/j.1476-5381.1992.tb09024.x. 
  7. ^ Hoffmann, O.; Wiesenfeld-Hallin, Z. (1994). „The CCK-B receptor antagonist Cl 988 reverses tolerance to morphine in rats”. NeuroReport. 7696605 (18): 2565—2568. PMID 7696605. doi:10.1097/00001756-199412000-00040. 
  8. ^ Maldonado, R.; Valverde, O.; Ducos, B.; Blommaert, A. G.; Fournie-Zaluski, M. C.; Roques, B. P. (1995). „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. 7780637 (5): 1031—1039. PMC 1510310Слободан приступ. PMID 7780637. doi:10.1111/j.1476-5381.1995.tb13309.x. 
  9. ^ Valverde, O.; Roques, B. P. (1998). „Cholecystokinin modulates the aversive component of morphine withdrawal syndrome in rats”. Neuroscience Letters. 9578139 (1): 37—40. PMID 9578139. S2CID 34384142. doi:10.1016/s0304-3940(98)00118-9. 
  10. ^ Bradwejn, J.; Koszycki, D.; Paradis, M.; Reece, P.; Hinton, J.; Sedman, A. (1995). „Effect of CI-988 on cholecystokinin tetrapeptide-induced panic symptoms in healthy volunteers”. Biological Psychiatry. 8580227 (11): 742—746. PMID 8580227. S2CID 1096074. doi:10.1016/0006-3223(95)00081-X. 
  11. ^ Adams, J. B.; Pyke, R. E.; Costa, J.; Cutler, N. R.; Schweizer, E.; Wilcox, C. S.; Wisselink, P. G.; Greiner, M.; Pierce, M. W.; Pande, A. C. (1995). „A double-blind, placebo-controlled study of a CCK-B receptor antagonist, CI-988, in patients with generalized anxiety disorder”. Journal of Clinical Psychopharmacology. 8748432 (6): 428—434. PMID 8748432. doi:10.1097/00004714-199512000-00007. 
  12. ^ Van Megen, H. J.; Westenberg, H. G.; Den Boer, J. A.; Slaap, B.; Van Es-Radhakishun, F.; Pande, A. C. (1997). „The cholecystokinin-B receptor antagonist CI-988 failed to affect CCK-4 induced symptoms in panic disorder patients”. Psychopharmacology. 9084062 (3): 243—248. PMID 9084062. S2CID 12570838. doi:10.1007/s002130050186. 
  13. ^ Goddard, A. W.; Woods, S. W.; Money, R.; Pande, A. C.; Charney, D. S.; Goodman, W. K.; Heninger, G. R.; Price, L. H. (1999). „Effects of the CCK(B) antagonist CI-988 on responses to MCPP in generalized anxiety disorder”. Psychiatry Research. 10333376 (3): 225—240. PMID 10333376. S2CID 140209273. doi:10.1016/s0165-1781(99)00015-3. 
  14. ^ Pande, A. C.; Greiner, M.; Adams, J. B.; Lydiard, R. B.; Pierce, M. W. (1999). „Placebo-controlled trial of the CCK-B antagonist, CI-988, in panic disorder”. Biological Psychiatry. 10494457 (6): 860—862. PMID 10494457. S2CID 5801419. doi:10.1016/s0006-3223(99)00090-6. 
  15. ^ Le Guen, S.; Mas Nieto, M.; Canestrelli, C.; Chen, H.; Fournié-Zaluski, M. C.; Cupo, A.; Maldonado, R.; Roques, B. P.; Noble, F. (2003). „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. 12855323 (1–2): 139—148. PMID 12855323. S2CID 38514264. doi:10.1016/s0304-3959(02)00486-4. 

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