title: (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent γ-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction.
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.
authors: Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208-3113, United States.
authors: Yue
authors: Y
authors: Pan
authors: Madina R
authors: MR
authors: Gerasimov
authors: Trine
authors: T
authors: Kvist
authors: Petrine
authors: P
authors: Wellendorph
authors: Karsten K
authors: KK
authors: Madsen
authors: Elena
authors: E
authors: Pera
authors: Hyunbeom
authors: H
authors: Lee
authors: Arne
authors: A
authors: Schousboe
authors: Mary
authors: M
authors: Chebib
authors: Hans
authors: H
authors: Bräuner-Osborne
authors: Cheryl M
authors: CM
authors: Craft
authors: Jonathan D
authors: JD
authors: Brodie
authors: Wynne K
authors: WK
authors: Schiffer
authors: Stephen L
authors: SL
authors: Dewey
authors: Steven R
authors: SR
authors: Miller
authors: Richard B
authors: RB
authors: Silverman
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D004285:Dogs; D004298:Dopamine / Q000378:metabolism; D004596:Electroretinography; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins / Q000502:physiology; D058805:GABA Uptake Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D008297:Male; D051379:Mice; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D049268:Positron-Emission Tomography; D011392:Proline / Q000031:analogs & derivatives; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D014018:Tissue Distribution; D020888:Vigabatrin / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: C519726:(1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid; D002264:Carboxylic Acids; D003517:Cyclopentanes; D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D018079:Receptors, GABA; D011392:Proline; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin; D004298:Dopamine