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

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Pan Y, Gerasimov MR, Kvist T, Wellendorph P, Madsen KK, Pera E, Lee H, Schousboe A, Chebib M, Brauner-Osborne H, Craft CM, Brodie JD, Schiffer WK, Dewey SL, Miller SR, Silverman RB

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

J Med Chem. 2012 Jan 12;55(1):357-66. doi: 10.1021/jm201231w. Epub 2011 Dec 30.

PubMed ID

22128851 [ View in PubMed

]

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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Vigabatrin	4-aminobutyrate aminotransferase, mitochondrial	Ki (nM)	3200000	N/A	N/A	Details