Chemistry:CI-966

From HandWiki
Revision as of 20:14, 5 February 2024 by Ohm (talk | contribs) (correction)
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
Short description: Chemical compound
CI-966
CI-966.svg
Clinical data
Routes of
administration		Oral
ATC code
  • None
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
Chemical and physical data
FormulaC23H21F6NO3
Molar mass473.415 g·mol−1
3D model (JSmol)

CI-966 (developmental code name) is a central nervous system depressant acting as a GABA reuptake inhibitor, specifically a highly potent and selective blocker of the GABA transporter 1 (GAT-1) (IC50 = 0.26 μM),[1] and hence indirect and non-selective GABA receptor full agonist.[2][3] It was investigated as a potential anticonvulsant, anxiolytic, and neuroprotective therapeutic but was discontinued during clinical development due to the incidence of severe adverse effects at higher doses and hence was never marketed.[2]

In a phase I human clinical trial while under development for the treatment of epilepsy, 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 produced memory deficits and the 50 mg dose was found to produce "a variety of severe neurological and psychiatric symptoms" and "serious psychotic adverse effects" of prolonged (several-day) duration and demonstrated "severe adverse CNS symptoms such as memory deficits, myoclonus and tremors, unresponsiveness and subsequent severe psychological disturbances".[2][4][5][6][7] The psychotomimetic effects produced by CI-966 are reportedly "similar to those of schizophrenia" and show "a similar phenotype to that seen with the psychotomimetics that block the effects of glutamate at the NMDA receptor",[8][9] and the psychiatric effects of CI-966 were also described as resembling those seen in patients with mania 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 a hallucinogen similarly to the potent GABAA receptor full agonist muscimol (a constituent of the hallucinogenic Amanita muscaria (fly agaric) mushrooms).[10]

In contrast to CI-966, the marketed selective GAT-1 blocker (and analogue 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 in pharmacology 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 anticonvulsant GABA 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

References

  1. ↑ GABA: Receptors, Transporters and Metabolism. Birkhäuser. 6 December 2012. pp. 70–. ISBN 978-3-0348-8990-2. https://books.google.com/books?id=xyn3BwAAQBAJ&pg=PA70. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Neurotherapeutics: Emerging Strategies. Springer Science & Business Media. 13 November 1995. pp. 93–94,207–208. ISBN 978-1-59259-466-5. https://books.google.com/books?id=HH71BwAAQBAJ&pg=PA208. 
  3. ↑ "GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke". Neuropharmacology 39 (9): 1483–1494. July 2000. doi:10.1016/S0028-3908(99)00233-6. PMID 10854894. 
  4. ↑ 4.0 4.1 4.2 "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. 1990. doi:10.1002/ddr.430210309. ISSN 0272-4391. 
  5. ↑ 5.0 5.1 Drug Discovery: Practices, Processes, and Perspectives. John Wiley & Sons. 3 April 2013. pp. 262–. ISBN 978-1-118-35446-9. https://books.google.com/books?id=mIyxO5cLEAcC&pg=PA262. 
  6. ↑ 6.0 6.1 "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. February 2005. doi:10.1124/jpet.104.068825. PMID 15550575. 
  7. ↑ 7.0 7.1 "Inhibitors of mammalian central nervous system selective amino acid transporters". Current Medicinal Chemistry 7 (2): 199–209. February 2000. doi:10.2174/0929867003375380. PMID 10637362. 
  8. ↑ Glutamate and GABA Receptors and Transporters: Structure, Function and Pharmacology. CRC Press. 4 October 2001. pp. 419–. ISBN 978-0-203-29938-8. https://books.google.com/books?id=7f0eC_olTJMC&pg=PA419. 
  9. ↑ "Schizophrenia". Comprehensive Medicinal Chemistry II: 17–44. 2007. doi:10.1016/B0-08-045044-X/00162-0. ISBN 9780080450445. 
  10. ↑ "New class of hallucinogens: GABA-enhancing agents". Drug Development Research 21 (3): 253–256. 1990. doi:10.1002/ddr.430210311. ISSN 0272-4391. 
  11. ↑ "GABA uptake inhibitors. Design, molecular pharmacology and therapeutic aspects". Current Pharmaceutical Design 6 (12): 1193–1209. August 2000. doi:10.2174/1381612003399608. PMID 10903390. 
  12. ↑ "Vigabatrin: 2008 update". Epilepsia 50 (2): 163–173. February 2009. doi:10.1111/j.1528-1167.2008.01988.x. PMID 19230067. 
  13. ↑ "Psychiatric adverse events during vigabatrin therapy". Neurology 53 (7): 1503–1511. October 1999. doi:10.1212/wnl.53.7.1503. PMID 10534259. 
  14. ↑ "Psychotic and severe behavioural reactions with vigabatrin: a review". Acta Neurologica Scandinavica 93 (1): 1–8. January 1996. doi:10.1111/j.1600-0404.1996.tb00161.x. PMID 8825264. 

Further reading

  • "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. October 1994. doi:10.1016/0922-4106(94)90089-2. PMID 7851497. 
  • "CI-966, a GABA uptake inhibitor, antagonizes ischemia-induced neuronal degeneration in the gerbil". General Pharmacology 26 (5): 1061–1064. September 1995. doi:10.1016/0306-3623(94)00270-W. PMID 7557251. 
  • "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. 1990. doi:10.1002/ddr.430210309. ISSN 0272-4391. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:CI-966&oldid=3321955"