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

被引：39

作者：

Pan, Yue ^{[1
,2
]}

Gerasimov, Madina R. ^{[3
]}

Kvist, Trine ^{[4
]}

Wellendorph, Petrine ^{[4
]}

Madsen, Karsten K. ^{[5
]}

Pera, Elena ^{[6
]}

Lee, Hyunbeom ^{[1
,2
]}

Schousboe, Arne ^{[5
]}

Chebib, Mary ^{[6
]}

Brauner-Osborne, Hans ^{[4
]}

Craft, Cheryl M. ^{[7
]}

Brodie, Jonathan D. ^{[8
]}

Schiffer, Wynne K. ^{[3
]}

Dewey, Stephen L. ^{[3
]}

Miller, Steven R. ^{[9
]}

Silverman, Richard B. ^{[1
,2
]}

机构：

[1] Northwestern Univ, Ctr Mol Innovat & Drug Discovery, Chem Life Proc Inst, Dept Chem, Evanston, IL 60208 USA

[2] Northwestern Univ, Ctr Mol Innovat & Drug Discovery, Chem Life Proc Inst, Dept Mol Biosci, Evanston, IL 60208 USA

[3] Feinstein Inst Med Res, N Shore LIJ Hlth Syst, Ctr Neurosci, Manhasset, NY 11030 USA

[4] Univ Copenhagen, Fac Pharmaceut Sci, Dept Med Chem, DK-2100 Copenhagen, Denmark

[5] Univ Copenhagen, Fac Pharmaceut Sci, Dept Pharmacol & Pharmacotherapy, DK-2100 Copenhagen, Denmark

[6] Univ Sydney, Fac Pharm, Sydney, NSW 2006, Australia

[7] Univ So Calif, Keck Sch Med, Doheny Eye Inst, Mary D Allen Lab Vis Res,Dept Ophthalmol & Cell &, Los Angeles, CA 90033 USA

[8] NYU, Sch Med, Dept Psychiat, New York, NY 10016 USA

[9] Catalyst Pharmaceut Partners Inc, Coral Gables, FL 33134 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 01期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

GABA-TRANSAMINASE INHIBITOR; NUCLEUS-ACCUMBENS DOPAMINE; VINYL-GABA; ANTICONVULSANT ACTIVITY; ANTIEPILEPTIC DRUGS; INDUCED INCREASES; FIELD LOSS; VIGABATRIN; BRAIN; RATS;

D O I：

10.1021/jm201231w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-cydopentanoic 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.

引用

页码：357 / 366

页数：10

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