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

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.
Authors	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
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 1 Pg. 357-66 (Jan 12 2012) ISSN: 1520-4804 [Electronic] United States
PMID	22128851 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	(1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid Carboxylic Acids Cyclopentanes GABA Plasma Membrane Transport Proteins GABA Uptake Inhibitors Receptors, GABA Proline 4-Aminobutyrate Transaminase Vigabatrin Dopamine
Topics	4-Aminobutyrate Transaminase (metabolism) Animals Biological Availability Carboxylic Acids (chemical synthesis, pharmacology, toxicity) Cocaine-Related Disorders (drug therapy, metabolism, psychology) Cyclopentanes (chemical synthesis, pharmacology, toxicity) Dogs Dopamine (metabolism) Electroretinography Female GABA Plasma Membrane Transport Proteins (physiology) GABA Uptake Inhibitors (chemical synthesis, pharmacology, toxicity) Humans Male Mice Microdialysis Nucleus Accumbens (drug effects, metabolism) Oocytes (drug effects, physiology) Positron-Emission Tomography Proline (analogs & derivatives) Radioligand Assay Rats Rats, Sprague-Dawley Rats, Wistar Receptors, GABA (metabolism) Retina (drug effects, physiology) Stereoisomerism Tissue Distribution Vigabatrin (pharmacology) Xenopus laevis

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