TY - JOUR
T1 - (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent gamma-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction
AU - Pan, Yue
AU - Gerasimov, Madina R
AU - Kvist, Trine
AU - Wellendorph, Petrine
AU - Madsen, Karsten Kirkegaard
AU - Pera, Elena
AU - Lee, Hyunbeom
AU - Schousboe, Arne
AU - Chebib, Mary
AU - Bräuner-Osborne, Hans
AU - Craft, Cheryl M
AU - Brodie, Jonathan D
AU - Schiffer, Wynne K
AU - Dewey, Stephen L
AU - Miller, Stephen R
AU - Silverman, Richard B
N1 - Keywords: GABA aminotransferase; enzyme inactivator; addiction; cocaine; visual
field defect; pharmacokinetics; micro-PET imaging; conditioned place preference
PY - 2012/1/12
Y1 - 2012/1/12
N2 - 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.
AB - 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.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1021/jm201231w
DO - 10.1021/jm201231w
M3 - Journal article
C2 - 22128851
SN - 0022-2623
VL - 55
SP - 357
EP - 366
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -