CI-988

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 broj	130332-27-3^Y
PubChem	CID 108186
Hemijski podaci
Formula	C₃₅H₄₂N₄O₆
Molarna masa	614.73 g/mol
SMILES 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 CCK_B 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 CCK_B antagonista na ljudima uprkos pozitivnih rezultata na životinjama nisu jasni. Slabe farmakokinetičke osobine su moguće objašnjenje,^[14] tako da se CCK_B antagonisti još uvek istražuju kao mogući pomoćni lekovi za pojačanje dejstva drugih lekova.^[15]

Reference

^ 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 54610 . PMID 1975695. doi:10.1073/pnas.87.17.6728 .
^ 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 1908271 . PMID 1686205. doi:10.1111/j.1476-5381.1991.tb12413.x.
^ 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 54692 . PMID 1698290. doi:10.1073/pnas.87.18.7105 .
^ 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.
^ 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.
^ 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 1908430 . PMID 1628146. doi:10.1111/j.1476-5381.1992.tb09024.x.
^ 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.
^ 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 1510310 . PMID 7780637. doi:10.1111/j.1476-5381.1995.tb13309.x.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.

Spoljašnje veze

Neuropeptidni ligandi

Holecistokinin

CCK_A	Agonisti: Holecistokinin • CCK-4 Antagonisti: Asperlicin • Proglumid • Lorglumid • Devazepid • Deksloksiglumid
CCK_B	Agonisti: Holecistokinin • CCK-4 • Gastrin Antagonisti: Proglumid • CI-988

CRH

CRF₁	Agonisti: Kortikotropin-oslobađajuči hormon Antagonisti: Antalarmin • CP-154,526 • Peksacerfont
CRF₂	Agonisti: Kortikotropin-oslobađajuči hormon

Galanin

GAL₁	Agonisti: Galanin • Galaninu-sličan peptid • Galmic • Galnon
GAL₂	Agonisti: Galanin • Galaninu-sličan peptid • Galmic • Galnon
GAL₃	Agonisti: Galanin • Galmic • Galnon

Grelin

Agonisti: Grelin • Kapromorelin • MK-677 • Sermorelin • SM-130,686 • Tabimorelin

MCH

MCH₁	Agonisti: Melanin-koncentrirajući hormon Antagonisti: ATC-0175 • GW-803,430 • NGD-4715 • SNAP-7941 • SNAP-94847
MCH₂	Agonisti: Melanin-koncentrirajući hormon

Melanokortin

MC₁	Agonisti: alfa-MSH • Afamelanotid • Bremelanotid • Melanotan II Antagonisti: Agouti signalni peptid
MC₂	Agonisti: ACTH • Kosintropin • Tetrakosaktid
MC₃	Agonisti: alfa-MSH • Bremelanotid • Melanotan II
MC₄	Agonisti: alfa-MSH • Bremelanotid • Melanotan II • THIQ Antagonisti: Agutiju srodni peptid
MC₅	Agonisti: alfa-MSH • Melanotan II

Neuropeptid S

Agonisti: Neuropeptid S
Antagonisti: SHA-68

Neuropeptid Y

Y₁	Agonisti: Neuropeptid Y • Peptid YY Antagonisti: BIBP-3226
Y₂	Agonisti: Neuropeptid Y • Peptid YY Antagonisti: BIIE-0246
Y₄	Agonisti: Neuropeptid Y • Pankreasni polipeptid • Peptid YY Antagonisti: UR-AK49
Y₅	Agonisti: Neuropeptid Y • Peptid YY Antagonisti: Lu AA-33810

Neurotenzin

NTS₁	Agonisti: Neurotenzin • Neuromedin N Antagonisti: SR-48692 • SR-142,948
NTS₂	Agonisti: Neurotenzin Antagonisti: Levokabastin • SR-142,948

Opioid

vidi Opioidi

Oreksin

OX₁	Agonisti: Oreksin-A Antagonisti: Almoreksant • SB-334,867 • SB-408,124 • SB-649,868
OX₂	Agonisti: Oreksin-A Antagonisti: Almoreksant • SB-649,868 • TCS-OX2-29

Oksitocin

Agonisti: Karbetocin • Demoksitocin • Oksitocin • WAY-267,464
Antagonisti: Atosiban • L-371,257 • L-368,899

Tahikinin

NK₁	Agonisti: Supstanca P Antagonisti: Aprepitant • Befetupitant • Kasopitant • CI-1021 • CP-96,345 • CP-99,994 • CP-122,721 • Dapitant • Ezlopitant • FK-888 • Fosaprepitant • GR-203,040 • GW-597,599 • HSP-117 • L-733,060 • L-741,671 • L-743,310 • L-758,298 • Lanepitant • LY-306,740 • Maropitant • Netupitant • NKP-608 • Nolpitantium • Orvepitant • RP-67,580 • SDZ NKT 343 • Vestipitant • Vofopitant
NK₂	Agonisti: Neurokinin A Antagonisti: GR-159897 • Ibodutant • Saredutant
NK₃	Agonisti: Neurokinin B Antagonisti: Osanetant • Talnetant

Vazopresin

V_1A	Agonisti: Dezmopresin • Felipresin • Ornipresin • Terlipresin • Vazopresin Antagonisti: Konivaptan • Demeklociklin • Relkovaptan
V_1B	Agonisti: Felipresin • Ornipresin • Terlipresin • Vazopresin Antagonisti: Demeklociklin • Nelivaptan
V₂	Agonisti: Dezmopresin • Ornipresin • Vazopresin Antagonisti: Konivaptan • Demeklociklin • Liksivaptan • Mozavaptan • Satavaptan • Tolvaptan