CI-966

{{Short description|Chemical compound}}

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| IUPAC_name = 1-(2-{bis[4-(trifluoromethyl)phenyl]methoxy}ethyl)-
-3,6-dihydro-2H-pyridine-5-carboxylic acid

| image = CI-966.svg

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| routes_of_administration = Oral

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| CAS_number_Ref =

| CAS_number = 110283-79-9

| CAS_supplemental =
110283-66-4 (HCl)

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 4HVE799MEJ

| ATC_prefix = None

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| PubChem = 198693

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| ChemSpiderID_Ref =

| ChemSpiderID = 171978

| IUPHAR_ligand = 4612

| C=23 | H=21 | F=6 | N=1 | O=3

| smiles = 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

| StdInChI_Ref =

| StdInChI = 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)

| StdInChIKey_Ref =

| StdInChIKey = CMHQDSBIBSKHFP-UHFFFAOYSA-N

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}}

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),{{cite book| vauthors = Tanaka C, Bowery NG |title=GABA: Receptors, Transporters and Metabolism|url=https://books.google.com/books?id=xyn3BwAAQBAJ&pg=PA70|date=6 December 2012|publisher=Birkhäuser|isbn=978-3-0348-8990-2|pages=70–}} and hence indirect and non-selective GABA receptor full agonist.{{cite book| vauthors = Pullan L, Patel J |title=Neurotherapeutics: Emerging Strategies|url=https://books.google.com/books?id=HH71BwAAQBAJ&pg=PA208|date=13 November 1995|publisher=Springer Science & Business Media|isbn=978-1-59259-466-5|pages=93–94,207–208}}{{cite journal | vauthors = Green AR, Hainsworth AH, Jackson DM | title = GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke | journal = Neuropharmacology | volume = 39 | issue = 9 | pages = 1483–1494 | date = July 2000 | pmid = 10854894 | doi = 10.1016/S0028-3908(99)00233-6 | s2cid = 39073036 }} 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.

In a phase I human clinical trial while under development for the treatment of epilepsy, CI-966 was assessed at doses of 1 to 10 mg, 25 mg, and 50 mg.{{cite journal| vauthors = Sedman AJ, Gilmet GP, Sayed AJ, Posvar EL |title=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|journal=Drug Development Research|volume=21|issue=3|year=1990|pages=235–242|issn=0272-4391|doi=10.1002/ddr.430210309|s2cid=84577983}} While the 1 to 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".{{cite book| vauthors = Li JJ, Corey EJ |title=Drug Discovery: Practices, Processes, and Perspectives|url=https://books.google.com/books?id=mIyxO5cLEAcC&pg=PA262|date=3 April 2013|publisher=John Wiley & Sons|isbn=978-1-118-35446-9|pages=262–}}{{cite journal | vauthors = White HS, Watson WP, Hansen SL, Slough S, Perregaard J, Sarup A, Bolvig T, Petersen G, Larsson OM, Clausen RP, Frølund B, Falch E, Krogsgaard-Larsen P, Schousboe A | display-authors = 6 | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 312 | issue = 2 | pages = 866–874 | date = February 2005 | pmid = 15550575 | doi = 10.1124/jpet.104.068825 | s2cid = 30717285 }}{{cite journal | vauthors = Armer RE | title = Inhibitors of mammalian central nervous system selective amino acid transporters | journal = Current Medicinal Chemistry | volume = 7 | issue = 2 | pages = 199–209 | date = February 2000 | pmid = 10637362 | doi = 10.2174/0929867003375380 }} 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",{{cite book| vauthors = Egebjerg J, Schousboe A, Krogsgaard-Larsen P |title=Glutamate and GABA Receptors and Transporters: Structure, Function and Pharmacology|url=https://books.google.com/books?id=7f0eC_olTJMC&pg=PA419|date=4 October 2001|publisher=CRC Press|isbn=978-0-203-29938-8|pages=419–}}{{cite journal| vauthors = Marino M, Davis R, Meltzer H, Knutsen L, Williams M |title=Schizophrenia|year=2007|pages=17–44|doi=10.1016/B0-08-045044-X/00162-0|journal=Comprehensive Medicinal Chemistry II|isbn=9780080450445}} and the psychiatric effects of CI-966 were also described as resembling those seen in patients with mania in addition to schizophrenia. These research findings were responsible for the discontinuation of the clinical development of CI-966. In addition, on the basis of these findings, the drug has been characterized as a hallucinogen similarly to the potent GABA_A receptor full agonist muscimol (a constituent of the hallucinogenic Amanita muscaria (fly agaric) mushrooms).{{cite journal| vauthors = Hollister LE |title=New class of hallucinogens: GABA-enhancing agents|journal=Drug Development Research|volume=21|issue=3|year=1990|pages=253–256|issn=0272-4391|doi=10.1002/ddr.430210311|s2cid=143868762}}

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. 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.{{cite journal | vauthors = Krogsgaard-Larsen P, Frølund B, Frydenvang K | title = GABA uptake inhibitors. Design, molecular pharmacology and therapeutic aspects | journal = Current Pharmaceutical Design | volume = 6 | issue = 12 | pages = 1193–1209 | date = August 2000 | pmid = 10903390 | doi = 10.2174/1381612003399608 }} 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.{{cite journal | vauthors = Willmore LJ, Abelson MB, Ben-Menachem E, Pellock JM, Shields WD | title = Vigabatrin: 2008 update | journal = Epilepsia | volume = 50 | issue = 2 | pages = 163–173 | date = February 2009 | pmid = 19230067 | doi = 10.1111/j.1528-1167.2008.01988.x | doi-access = | s2cid = 26494867 }}{{cite journal | vauthors = Levinson DF, Devinsky O | title = Psychiatric adverse events during vigabatrin therapy | journal = Neurology | volume = 53 | issue = 7 | pages = 1503–1511 | date = October 1999 | pmid = 10534259 | doi = 10.1212/wnl.53.7.1503 }}{{cite journal | vauthors = Ferrie CD, Robinson RO, Panayiotopoulos CP | title = Psychotic and severe behavioural reactions with vigabatrin: a review | journal = Acta Neurologica Scandinavica | volume = 93 | issue = 1 | pages = 1–8 | date = January 1996 | pmid = 8825264 | doi = 10.1111/j.1600-0404.1996.tb00161.x | s2cid = 40041098 | doi-access = free }}

The onset of CI-966 is 45{{nbsp}}minutes, peak effects occur at 6 to 8{{nbsp}}hours, and its duration is 24{{nbsp}}hours. However, the time course of its effects is said to be dose-dependent.