(1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent gamma-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction

Research output: Contribution to journalJournal articleResearchpeer-review

Yue Pan, Madina R Gerasimov, Trine Kvist, Petrine Wellendorph, Karsten Kirkegaard Madsen, Elena Pera, Hyunbeom Lee, Arne Schousboe, Mary Chebib, Hans Bräuner-Osborne, Cheryl M Craft, Jonathan D Brodie, Wynne K Schiffer, Stephen L Dewey, Stephen R Miller, Richard B Silverman

Vigabatrin, a GABA aminotransferase (GABA-AT) inactivator, is used to treat infantile spasms and refractory complex partial seizures and is in clinical trials to treat addiction. We evaluated a novel GABA-AT inactivator (CPP-115) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. Using in vivo microdialysis techniques in freely moving rats and micro-PET imaging techniques, CPP-115 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at 1/300-1/600th the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose 1/300th that of vigabatrin. Electroretinographic (ERG) responses in rats treated with CPP-115, at doses 20-40 times higher than those needed to treat addiction in rats, exhibited reductions in ERG responses, which were less than the reductions observed in rats treated with vigabatrin at the same dose needed to treat addiction in rats. In conclusion, CPP-115 can be administered at significantly lower doses than vigabatrin, which suggests a potential new treatment for addiction with a significantly reduced risk of visual field defects.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume55
Issue number1
Pages (from-to)357-366
ISSN0022-2623
DOIs
Publication statusPublished - 1 Jan 2012

Bibliographical note

Keywords: GABA aminotransferase; enzyme inactivator; addiction; cocaine; visual
field defect; pharmacokinetics; micro-PET imaging; conditioned place preference

ID: 35438191