(1S, 3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Cocaine Addiction
(1S, 3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Cocaine Addiction
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DOI：
10.1021/jm201231w
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发表时间：
2012-01-12
影响因子：
7.3
通讯作者：
Silverman, Richard B.
中科院分区：
文献类型：
--
作者：
Pan, Yue;Gerasimov, Madina R.;Silverman, Richard B.
氨己烯酸是一种GABA氨基转移酶（GABA-AT）灭活剂，用于治疗婴儿痉挛和难治性复杂部分性癫痫发作，并正在进行治疗成瘾的临床试验。我们评价了一种新型GABA-AT灭活剂（1 S，3S）-3-氨基-4-二氟亚甲基-1-环戊酸（CPP-115，化合物1），并观察到它不显示其他GABA能或脱靶活性，并且快速完全口服吸收和消除。通过在自由活动的大鼠中使用体内微透析技术和microPET成像技术，在1/300至1/600剂量的氨己烯酸时，1对可卡因诱导的细胞外多巴胺和突触多巴胺增加产生了类似的抑制作用。它还阻断可卡因诱导的条件性位置偏爱的表达，剂量为氨己烯酸的1/300。用1（其剂量比治疗大鼠成瘾所需的剂量高20-40倍）治疗的大鼠中的视网膜电图（ERG）反应显示ERG反应的降低，其低于用氨己烯酸治疗大鼠成瘾所需的相同剂量治疗的大鼠中观察到的降低。总之，1可以以比氨己烯酸显著更低的剂量施用，这表明一种潜在的新的治疗成瘾的方法，其视野缺陷的风险显著降低。
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.