(1S, 3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a Potent 纬-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Cocaine Addiction

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• 作者：Yue Pan ; Madina R. Gerasimov ; Trine Kvist ; Petrine Wellendorph ; Karsten K. Madsen ; Elena Pera ; Hyunbeom Lee ; Arne Schousboe ; Mary Chebib ; Hans Br盲uner-Osborne ; Cheryl M. Craft ; Jonathan D. Brodie ; Wynne K. Schiffer ; Stephen L. Dewey ; Steven R. Miller ; Richard B. Silverman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 12, 2012
• 年：2012
• 卷：55
• 期：1
• 页码：357-366
• 全文大小：357K
• 年卷期：v.55,no.1(January 12, 2012)
• ISSN：1520-4804

文摘

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鈥?0 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.