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

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

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Abstract

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 (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115, compound 1) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. By use of in vivo microdialysis techniques in freely moving rats and microPET imaging techniques, 1 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at 1/ 300 to 1/ 600 the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose 1/ 300 that of vigabatrin. Electroretinographic (ERG) responses in rats treated with 1, 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, 1 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 (US)
Pages (from-to)357-366
Number of pages10
JournalJournal of medicinal chemistry
Volume55
Issue number1
DOIs
StatePublished - Jan 12 2012

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Pan, Y., Gerasimov, M. R., Kvist, T., Wellendorph, P., Madsen, K. K., Pera, E., Lee, H., Schousboe, A., Chebib, M., Bräuner-Osborne, H., Craft, C. M., Brodie, J. D., Schiffer, W. K., Dewey, S. L., Miller, S. R., & Silverman, R. B. (2012). (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent γ-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction. Journal of medicinal chemistry, 55(1), 357-366. https://doi.org/10.1021/jm201231w