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CI-966

From Wikipedia, the free encyclopedia
Chemical compound

Pharmaceutical compound
CI-966
Clinical data
Routes of
administration
Oral
ATC code
  • None
Identifiers
  • 1-(2-{bis[4-(trifluoromethyl)phenyl]methoxy}ethyl)-
    -3,6-dihydro-2H-pyridine-5-carboxylic acid
CAS Number
PubChemCID
IUPHAR/BPS
ChemSpider
UNII
CompTox Dashboard(EPA)
Chemical and physical data
FormulaC23H21F6NO3
Molar mass473.415 g·mol−1
3D model (JSmol)
  • C1CN(CC(=C1)C(=O)O)CCOC(C2=CC=C(C=C2)C(F)(F)F)C3=CC=C(C=C3)C(F)(F)F
  • InChI=InChI=1S/C23H21F6NO3/c24-22(25,26)18-7-3-15(4-8-18)20(16-5-9-19(10-6-16)23(27,28)29)33-13-12-30-11-1-2-17(14-30)21(31)32/h2-10,20H,1,11-14H2,(H,31,32)
  • Key:CMHQDSBIBSKHFP-UHFFFAOYSA-N

CI-966 (developmental code name) is acentral nervous systemdepressant acting as aGABA reuptake inhibitor, specifically a highly potent and selectiveblocker of theGABA transporter 1 (GAT-1) (IC50 = 0.26 μM),[1] and hence indirect and non-selectiveGABA receptorfull agonist.[2][3] It was investigated as a potentialanticonvulsant,anxiolytic, andneuroprotective therapeutic but was discontinued during clinical development due to the incidence of severeadverse effects at higher doses and hence was never marketed.[2]

In aphase I humanclinical trial while under development for the treatment ofepilepsy, CI-966 was assessed at doses of 1–10 mg, 25 mg, and 50 mg.[4] While the 1–10 mg dosages were well tolerated, the 25 mg dose producedmemory deficits and the 50 mg dose was found to produce "a variety of severe neurological and psychiatric symptoms" and "seriouspsychotic adverse effects" of prolonged (several-day) duration and demonstrated "severe adverse CNS symptoms such as memory deficits,myoclonus andtremors,unresponsiveness and subsequent severe psychological disturbances".[2][4][5][6][7] Thepsychotomimetic effects produced by CI-966 are reportedly "similar to those ofschizophrenia" and show "a similarphenotype to that seen with the psychotomimetics that block the effects ofglutamate at theNMDA receptor",[8][9] and the psychiatric effects of CI-966 were also described as resembling those seen in patients withmania in addition to schizophrenia.[4] These research findings were responsible for the discontinuation of the clinical development of CI-966.[2][5][7] In addition, on the basis of these findings, the drug has been characterized as ahallucinogen similarly to the potentGABAA receptor full agonistmuscimol (a constituent of the hallucinogenicAmanita muscaria (fly agaric) mushrooms).[10]

In contrast to CI-966, the marketed selective GAT-1 blocker (andanalogue of CI-966)tiagabine has been found at the dosages in which it has been studied and used to have far lower although non-absent potential for the same adverse effects of the former, including psychotic reactions.[6] This may be due to differences inpharmacology or potency between CI-966 and tiagabine or might be accounted for the possibility that the initial doses of CI-966 studied in humans simply were too high.[2][11] In addition to tiagabine, the marketed anticonvulsantGABA transaminase (GABA-T)inhibitor (and hence also an indirect and non-selective GABA receptor agonist)vigabatrin has also been associated with acute psychotic episodes,hallucinations, and other psychiatric adverse reactions, albeit less commonly.[12][13][14]

See also

[edit]

References

[edit]
  1. ^Tanaka C, Bowery NG (6 December 2012).GABA: Receptors, Transporters and Metabolism. Birkhäuser. pp. 70–.ISBN 978-3-0348-8990-2.
  2. ^abcdePullan L, Patel J (13 November 1995).Neurotherapeutics: Emerging Strategies. Springer Science & Business Media. pp. 93–94,207–208.ISBN 978-1-59259-466-5.
  3. ^Green AR, Hainsworth AH, Jackson DM (July 2000). "GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke".Neuropharmacology.39 (9):1483–1494.doi:10.1016/S0028-3908(99)00233-6.PMID 10854894.S2CID 39073036.
  4. ^abcSedman AJ, Gilmet GP, Sayed AJ, Posvar EL (1990). "Initial human safety and tolerance study of a GABA uptake inhibitor, Cl-966: Potential role of GABA as a mediator in the pathogenesis of schizophrenia and mania".Drug Development Research.21 (3):235–242.doi:10.1002/ddr.430210309.ISSN 0272-4391.S2CID 84577983.
  5. ^abLi JJ, Corey EJ (3 April 2013).Drug Discovery: Practices, Processes, and Perspectives. John Wiley & Sons. pp. 262–.ISBN 978-1-118-35446-9.
  6. ^abWhite HS, Watson WP, Hansen SL, Slough S, Perregaard J, Sarup A, et al. (February 2005). "First demonstration of a functional role for central nervous system betaine/{gamma}-aminobutyric acid transporter (mGAT2) based on synergistic anticonvulsant action among inhibitors of mGAT1 and mGAT2".The Journal of Pharmacology and Experimental Therapeutics.312 (2):866–874.doi:10.1124/jpet.104.068825.PMID 15550575.S2CID 30717285.
  7. ^abArmer RE (February 2000). "Inhibitors of mammalian central nervous system selective amino acid transporters".Current Medicinal Chemistry.7 (2):199–209.doi:10.2174/0929867003375380.PMID 10637362.
  8. ^Egebjerg J, Schousboe A, Krogsgaard-Larsen P (4 October 2001).Glutamate and GABA Receptors and Transporters: Structure, Function and Pharmacology. CRC Press. pp. 419–.ISBN 978-0-203-29938-8.
  9. ^Marino M, Davis R, Meltzer H, Knutsen L, Williams M (2007). "Schizophrenia".Comprehensive Medicinal Chemistry II:17–44.doi:10.1016/B0-08-045044-X/00162-0.ISBN 9780080450445.
  10. ^Hollister LE (1990). "New class of hallucinogens: GABA-enhancing agents".Drug Development Research.21 (3):253–256.doi:10.1002/ddr.430210311.ISSN 0272-4391.S2CID 143868762.
  11. ^Krogsgaard-Larsen P, Frølund B, Frydenvang K (August 2000). "GABA uptake inhibitors. Design, molecular pharmacology and therapeutic aspects".Current Pharmaceutical Design.6 (12):1193–1209.doi:10.2174/1381612003399608.PMID 10903390.
  12. ^Willmore LJ, Abelson MB, Ben-Menachem E, Pellock JM, Shields WD (February 2009). "Vigabatrin: 2008 update".Epilepsia.50 (2):163–173.doi:10.1111/j.1528-1167.2008.01988.x.PMID 19230067.S2CID 26494867.
  13. ^Levinson DF, Devinsky O (October 1999). "Psychiatric adverse events during vigabatrin therapy".Neurology.53 (7):1503–1511.doi:10.1212/wnl.53.7.1503.PMID 10534259.
  14. ^Ferrie CD, Robinson RO, Panayiotopoulos CP (January 1996)."Psychotic and severe behavioural reactions with vigabatrin: a review".Acta Neurologica Scandinavica.93 (1):1–8.doi:10.1111/j.1600-0404.1996.tb00161.x.PMID 8825264.S2CID 40041098.

Further reading

[edit]
  • Borden LA, Murali Dhar TG, Smith KE, Weinshank RL, Branchek TA, Gluchowski C (October 1994). "Tiagabine, SK&F 89976-A, CI-966, and NNC-711 are selective for the cloned GABA transporter GAT-1".European Journal of Pharmacology.269 (2):219–224.doi:10.1016/0922-4106(94)90089-2.PMID 7851497.
  • Phillis JW (September 1995). "CI-966, a GABA uptake inhibitor, antagonizes ischemia-induced neuronal degeneration in the gerbil".General Pharmacology.26 (5):1061–1064.doi:10.1016/0306-3623(94)00270-W.PMID 7557251.
  • Sedman AJ, Gilmet GP, Sayed AJ, Posvar EL (1990). "Initial human safety and tolerance study of a GABA uptake inhibitor, Cl-966: Potential role of GABA as a mediator in the pathogenesis of schizophrenia and mania".Drug Development Research.21 (3):235–242.doi:10.1002/ddr.430210309.ISSN 0272-4391.S2CID 84577983.
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