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

Yue Pan; Madina R Gerasimov; Trine Kvist; Petrine Wellendorph; Karsten Kirkegaard Madsen; Elena Pera; Hyunbeom Lee; Arne Schousboe; Mary Chebib; Hans Bräuner-Osborne; Cheryl M Craft; Jonathan D Brodie; Wynne K Schiffer; Stephen L Dewey; Stephen R Miller; Richard B Silverman

doi:10.1021/jm201231w

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

Yue Pan, Madina R Gerasimov, Trine Kvist, Petrine Wellendorph, Karsten Kirkegaard Madsen, Elena Pera, Hyunbeom Lee, Arne Schousboe, Mary Chebib, Hans Bräuner-Osborne, Cheryl M Craft, Jonathan D Brodie, Wynne K Schiffer, Stephen L Dewey, Stephen R Miller, Richard B Silverman

Research output: Contribution to journal › Journal article › Research › peer-review

41 Citations (Scopus)

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 (CPP-115) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. Using in vivo microdialysis techniques in freely moving rats and micro-PET imaging techniques, CPP-115 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at 1/300-1/600th the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose 1/300th that of vigabatrin. Electroretinographic (ERG) responses in rats treated with CPP-115, 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, CPP-115 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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	1
Pages (from-to)	357-366
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm201231w
Publication status	Published - 1 Jan 2012

Bibliographical note

Keywords: GABA aminotransferase; enzyme inactivator; addiction; cocaine; visual
field defect; pharmacokinetics; micro-PET imaging; conditioned place preference

Keywords

Former Faculty of Pharmaceutical Sciences

Access to Document

10.1021/jm201231w

Cite this

Pan, Y., Gerasimov, M. R., Kvist, T., Wellendorph, P., Madsen, K. K., Pera, E., Lee, H., Schousboe, A., Chebib, M., Bräuner-Osborne, H., Craft, C. M., Brodie, J. D., Schiffer, W. K., Dewey, S. L., Miller, S. R., & Silverman, R. B. (2012). (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent gamma-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction. Journal of Medicinal Chemistry, 55(1), 357-366. https://doi.org/10.1021/jm201231w

(1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent gamma-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction. / Pan, Yue; Gerasimov, Madina R; Kvist, Trine; Wellendorph, Petrine; Madsen, Karsten Kirkegaard; Pera, Elena; Lee, Hyunbeom; Schousboe, Arne; Chebib, Mary; Bräuner-Osborne, Hans; Craft, Cheryl M; Brodie, Jonathan D; Schiffer, Wynne K; Dewey, Stephen L; Miller, Stephen R; Silverman, Richard B.

In: Journal of Medicinal Chemistry, Vol. 55, No. 1, 01.01.2012, p. 357-366.

Research output: Contribution to journal › Journal article › Research › peer-review

Pan, Y, Gerasimov, MR, Kvist, T, Wellendorph, P, Madsen, KK, Pera, E, Lee, H, Schousboe, A, Chebib, M, Bräuner-Osborne, H, Craft, CM, Brodie, JD, Schiffer, WK, Dewey, SL, Miller, SR & Silverman, RB 2012, '(1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent gamma-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction', Journal of Medicinal Chemistry, vol. 55, no. 1, pp. 357-366. https://doi.org/10.1021/jm201231w

Pan, Yue ; Gerasimov, Madina R ; Kvist, Trine ; Wellendorph, Petrine ; Madsen, Karsten Kirkegaard ; Pera, Elena ; Lee, Hyunbeom ; Schousboe, Arne ; Chebib, Mary ; Bräuner-Osborne, Hans ; Craft, Cheryl M ; Brodie, Jonathan D ; Schiffer, Wynne K ; Dewey, Stephen L ; Miller, Stephen R ; Silverman, Richard B. / (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent gamma-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 1. pp. 357-366.

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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 (CPP-115) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. Using in vivo microdialysis techniques in freely moving rats and micro-PET imaging techniques, CPP-115 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at 1/300-1/600th the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose 1/300th that of vigabatrin. Electroretinographic (ERG) responses in rats treated with CPP-115, 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, CPP-115 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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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 - 2012/1/1

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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 (CPP-115) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. Using in vivo microdialysis techniques in freely moving rats and micro-PET imaging techniques, CPP-115 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at 1/300-1/600th the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose 1/300th that of vigabatrin. Electroretinographic (ERG) responses in rats treated with CPP-115, 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, CPP-115 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 (CPP-115) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. Using in vivo microdialysis techniques in freely moving rats and micro-PET imaging techniques, CPP-115 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at 1/300-1/600th the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose 1/300th that of vigabatrin. Electroretinographic (ERG) responses in rats treated with CPP-115, 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, CPP-115 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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