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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〔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〕〔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〕 and potentiated the analgesic action of both morphine〔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〕 and endogenous opioid peptides,〔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〕〔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〕 as well as preventing the development of tolerance to opioids〔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〕〔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〕 and reducing symptoms of withdrawal.〔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〕〔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〕 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.〔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〕〔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〕〔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〕〔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〕 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,〔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〕 and CCKB antagonists are still being researched for possible uses as adjuvants to boost the activity of other drugs.〔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. PMID 12855323〕
==References==
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