CI-966 (original) (raw)
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), and hence indirect and non-selective GABA receptor full agonist. 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.
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|---|---|
| dbo:abstract | 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), and hence indirect and non-selective GABA receptor full agonist. 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 1–10 mg, 25 mg, and 50 mg. 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". 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", 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 GABAA receptor full agonist muscimol (a constituent of the hallucinogenic Amanita muscaria (fly agaric) mushrooms). 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. 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. (en) |
| dbo:casNumber | 110283-66-4 (HCl) 110283-79-9 |
| dbo:fdaUniiCode | 4HVE799MEJ |
| dbo:pubchem | 198693 |
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| dbo:wikiPageWikiLink | dbr:Psychosis dbr:Psychotomimetic dbr:Schizophrenia dbr:Enzyme_inhibitor dbr:Epilepsy dbr:Anticonvulsant dbc:GABA_reuptake_inhibitors dbr:Pharmacology dbr:Vigabatrin dbr:Depressant dbr:Structural_analog dbr:GABA_transaminase dbc:Abandoned_drugs dbc:Carboxylic_acids dbc:Tetrahydropyridines dbc:Trifluoromethyl_compounds dbr:Coma dbr:SKF-89976A dbr:Oral_administration dbr:Full_agonist dbr:GABA_transporter_1 dbr:Gaboxadol dbr:Muscimol dbr:Myoclonus dbr:NNC-711 dbr:Anxiolytic dbr:Clinical_trial dbr:Hallucination dbr:Tiagabine dbr:Tremor dbr:GABAA_receptor dbr:GABA_receptor dbr:GABA_reuptake_inhibitor dbc:Anxiolytics dbc:Neuroprotective_agents dbr:Amanita_muscaria dbr:Nipecotic_acid dbr:Central_nervous_system dbr:Isoguvacine dbc:Anticonvulsants dbr:Guvacine dbr:Hallucinogen dbr:Isonipecotic_acid dbr:Hydrochloride dbr:Adverse_effect dbr:Phenotype dbr:Mania dbr:IC50 dbr:Phases_of_clinical_research dbr:NMDA_receptor dbr:Neuroprotective dbr:Transporter_blocker dbr:Glutamate dbr:Memory_deficit |
| dbp:atcPrefix | None (en) |
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| dbp:casNumber | 110283 (xsd:integer) |
| dbp:casSupplemental | 110283 (xsd:integer) |
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| dbp:pubchem | 198693 (xsd:integer) |
| dbp:routesOfAdministration | dbr:Oral_administration |
| dbp:smiles | C1CNCCOCC3=CC=CCF (en) |
| dbp:stdinchi | InChI=1S/C23H21F6NO3/c24-2218-7-3-152033-13-12-30-11-1-2-172132/h2-10,20H,1,11-14H2, (en) |
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| gold:hypernym | dbr:Anticonvulsant |
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| rdfs:comment | 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), and hence indirect and non-selective GABA receptor full agonist. 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. (en) |
| rdfs:label | CI-966 (en) |
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