CI-988

CI-988 (PD-134,308) is a drug which acts as a cholecystokinin antagonist, selective for the CCKB subtype. In animal studies it showed anxiolytic effects[1][2] and potentiated the analgesic action of both morphine[3] and endogenous opioid peptides,[4][5] as well as preventing the development of tolerance to opioids[6][7] and reducing symptoms of withdrawal.[8][9] Consequently, it was hoped that it might have clinical applications for the treatment of pain and anxiety in humans, but trial results were disappointing with only minimal therapeutic effects observed even at high doses.[10][11][12][13] The reason for the failure of CI-988 and other CCKB antagonists in humans despite their apparent promise in pre-clinical animal studies is unclear, although poor pharmacokinetic properties of the currently available drugs are a possible explanation,[14] and CCKB antagonists are still being researched for possible uses as adjuvants to boost the activity of other drugs.[15]

CI-988
Identifiers
IUPAC name
  • 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
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC35H42N4O6
Molar mass614.743 g·mol−1
3D model (JSmol)
SMILES
  • C[C@@](Cc1c[nH]c2c1cccc2)(C(=O)NC[C@@H](c3ccccc3)NC(=O)CCC(=O)O)NC(=O)OC4C5CC6CC(C5)CC4C6
InChI
  • InChI=1S/C35H42N4O6/c1-35(18-26-19-36-28-10-6-5-9-27(26)28,39-34(44)45-32-24-14-21-13-22(16-24)17-25(32)15-21)33(43)37-20-29(23-7-3-2-4-8-23)38-30(40)11-12-31(41)42/h2-10,19,21-22,24-25,29,32,36H,11-18,20H2,1H3,(H,37,43)(H,38,40)(H,39,44)(H,41,42)/t21?,22?,24?,25?,29-,32?,35+/m0/s1
  • Key:FVQSSYMRZKLFDR-ZABPBAJSSA-N
  (verify)

References
  1. Hughes J, Boden P, Costall B, Domeney A, Kelly E, Horwell DC, et al. (September 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. 87 (17): 6728–32. Bibcode:1990PNAS...87.6728H. doi:10.1073/pnas.87.17.6728. PMC 54610. PMID 1975695.
  2. Singh L, Field MJ, Hughes J, Menzies R, Oles RJ, Vass CA, Woodruff GN (September 1991). "The behavioural properties of CI-988, a selective cholecystokininB receptor antagonist". British Journal of Pharmacology. 104 (1): 239–45. doi:10.1111/j.1476-5381.1991.tb12413.x. PMC 1908271. PMID 1686205.
  3. Wiesenfeld-Hallin Z, Xu XJ, Hughes J, Horwell DC, Hökfelt T (September 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. 87 (18): 7105–9. Bibcode:1990PNAS...87.7105W. doi:10.1073/pnas.87.18.7105. PMC 54692. PMID 1698290.
  4. Durieux C, Derrien M, Maldonado R, Valverde O, Blommaert A, Fournié-Zaluski MC, Roques BP (March 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. 713: 355–7. doi:10.1111/j.1749-6632.1994.tb44091.x. PMID 8185186. S2CID 23317834.
  5. Valverde O, Maldonado R, Fournie-Zaluski MC, Roques BP (July 1994). "Cholecystokinin B antagonists strongly potentiate antinociception mediated by endogenous enkephalins". The Journal of Pharmacology and Experimental Therapeutics. 270 (1): 77–88. PMID 8035345.
  6. Xu XJ, Wiesenfeld-Hallin Z, Hughes J, Horwell DC, Hökfelt T (March 1992). "CI988, a selective antagonist of cholecystokininB receptors, prevents morphine tolerance in the rat". British Journal of Pharmacology. 105 (3): 591–6. doi:10.1111/j.1476-5381.1992.tb09024.x. PMC 1908430. PMID 1628146.
  7. Hoffmann O, Wiesenfeld-Hallin Z (December 1994). "The CCK-B receptor antagonist Cl 988 reverses tolerance to morphine in rats". NeuroReport. 5 (18): 2565–8. doi:10.1097/00001756-199412000-00040. PMID 7696605.
  8. Maldonado R, Valverde O, Ducos B, Blommaert AG, Fournie-Zaluski MC, Roques BP (March 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. 114 (5): 1031–9. doi:10.1111/j.1476-5381.1995.tb13309.x. PMC 1510310. PMID 7780637.
  9. Valverde O, Roques BP (March 1998). "Cholecystokinin modulates the aversive component of morphine withdrawal syndrome in rats". Neuroscience Letters. 244 (1): 37–40. doi:10.1016/s0304-3940(98)00118-9. PMID 9578139. S2CID 34384142.
  10. Bradwejn J, Koszycki D, Paradis M, Reece P, Hinton J, Sedman A (December 1995). "Effect of CI-988 on cholecystokinin tetrapeptide-induced panic symptoms in healthy volunteers". Biological Psychiatry. 38 (11): 742–6. doi:10.1016/0006-3223(95)00081-X. PMID 8580227. S2CID 1096074.
  11. Adams JB, Pyke RE, Costa J, Cutler NR, Schweizer E, Wilcox CS, et al. (December 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. 15 (6): 428–34. doi:10.1097/00004714-199512000-00007. PMID 8748432.
  12. van Megen HJ, Westenberg HG, den Boer JA, Slaap B, van Es-Radhakishun F, Pande AC (February 1997). "The cholecystokinin-B receptor antagonist CI-988 failed to affect CCK-4 induced symptoms in panic disorder patients". Psychopharmacology. 129 (3): 243–8. doi:10.1007/s002130050186. PMID 9084062. S2CID 12570838.
  13. Goddard AW, Woods SW, Money R, Pande AC, Charney DS, Goodman WK, et al. (March 1999). "Effects of the CCK(B) antagonist CI-988 on responses to mCPP in generalized anxiety disorder". Psychiatry Research. 85 (3): 225–40. doi:10.1016/s0165-1781(99)00015-3. PMID 10333376. S2CID 140209273.
  14. Pande AC, Greiner M, Adams JB, Lydiard RB, Pierce MW (September 1999). "Placebo-controlled trial of the CCK-B antagonist, CI-988, in panic disorder". Biological Psychiatry. 46 (6): 860–2. doi:10.1016/s0006-3223(99)00090-6. PMID 10494457. S2CID 5801419.
  15. Le Guen S, Mas Nieto M, Canestrelli C, Chen H, Fournié-Zaluski MC, Cupo A, et al. (July 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. 104 (1–2): 139–48. doi:10.1016/s0304-3959(02)00486-4. PMID 12855323. S2CID 38514264.
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