R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse.
R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse.
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DOI：
10.1016/j.biopsych.2012.03.022
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发表时间：
2012-09-01
影响因子：
10.6
通讯作者：
Newman, Amy Hauck
中科院分区：
文献类型：
--
作者：
Loland, Claus J.;Mereu, Maddalena;Okunola, Oluyomi M.;Cao, Jianjing;Prisinzano, Thomas E.;Mazier, Sonia;Kopajtic, Theresa;Shi, Lei;Katz, Jonathan L.;Tanda, Gianluigi;Newman, Amy Hauck
（±）-莫达非尼作为ADHD和兴奋剂依赖的治疗引起了人们的兴趣。莫达非尼的r -对映体可能具有独特的药理学性质，值得进一步研究。合成了（±）-莫达非尼及其R-(−)-和S-(+)-对映体，并测试了hDAT WT和构象平衡改变的突变体对[3H]DA摄取和[3H]WIN 35,428结合的抑制作用。将数据与可卡因和非典型多巴胺摄取抑制剂JHW 007进行比较。R-和s -莫达非尼也在小鼠NAc壳的微透析研究和可卡因鉴别程序中进行了评估。（±）-、R-和s -莫达非尼与DAT结合并抑制多巴胺摄取的效力低于可卡因，R-莫达非尼的亲和力比s -对映体高3倍。分子对接研究揭示了对映体结合模式的细微差异。与野生型DAT相比，r -莫达非尼对DAT Y156F突变体的作用明显减弱，而s -莫达非尼受影响较小。对Y335A DAT突变体的研究表明，R-和s -对映体比可卡因更能耐受内向构象，MTSET对DAT E2C I159C的反应性进一步支持了这一点。微透析研究表明，R-莫达非尼和s -莫达非尼在NAc壳中产生的细胞外DA浓度的增加不如可卡因有效，且作用持续时间更长。这两种对映异构体在老鼠身上被完全取代，训练它们区分可卡因和生理盐水。r -莫达非尼在体外表现出与可卡因不同的特征。未来的试验将r -莫达非尼作为一种替代疗法，对精神兴奋剂成瘾具有潜在的认知增强益处。
(±)-Modafinil has piqued interest as a treatment for ADHD and stimulant dependence. The R-enantiomer of modafinil may have unique pharmacological properties that should be further investigated. (±)-Modafinil and its R-(−)- and S-(+)-enantiomers were synthesized and tested for inhibition of [3H]DA uptake and [3H]WIN 35,428 binding in hDAT WT and mutants with altered conformational equilibria. Data were compared to cocaine and the atypical dopamine uptake inhibitor, JHW 007. R- and S-modafinil were also evaluated in microdialysis studies in the mouse NAc shell and in a cocaine discrimination procedure. (±)-, R- and S-Modafinil bind to the DAT and inhibit dopamine uptake less potently than cocaine, with R-modafinil having ~3-fold higher affinity than its S-enantiomer. Molecular docking studies revealed subtle differences in binding modes for the enantiomers. R-modafinil was significantly less potent in the DAT Y156F mutant compared to wild-type DAT, whereas S-modafinil was affected less. Studies with the Y335A DAT mutant showed that the R- and S-enantiomers tolerated the inward facing conformation better than cocaine, which was further supported by MTSET reactivity on the DAT E2C I159C. Microdialysis studies demonstrated that both R- and S-modafinil produced increases in extracellular DA concentrations in the NAc shell less efficaciously than cocaine, and with a longer duration of action. Both enantiomers fully substituted in mice trained to discriminate cocaine from saline. R-modafinil displays an in vitro profile different from cocaine. Future trials with R-modafinil as a substitute therapy with the potential benefit of cognitive enhancement for psychostimulant addiction are warranted.
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DOI：
10.1016/j.pbb.2011.04.017
发表时间：
2011-08
期刊：
Pharmacology, biochemistry, and behavior
影响因子：
--
作者：
Brady KT;Gray KM;Tolliver BK
通讯作者：
Tolliver BK
影响因子：
2.3
作者：
Goulet, M;Miller, GM;Madras, BK
通讯作者：
Madras, BK
影响因子：
4.2
作者：
Cao, Jianjing;Prisinzano, Thomas E.;Okunola, Oluyomi M.;Kopajtic, Theresa;Shook, Matthew;Katz, Jonathan L.;Newman, Amy Hauck
通讯作者：
Newman, Amy Hauck
影响因子：
3.4
作者：
Deroche-Gamonet, V;Darnaudéry, M;Piazza, PV
通讯作者：
Piazza, PV
影响因子：
4.7
作者：
Bisgaard, Heidi;Larsen, M. Andreas B.;Mazier, Sonia;Beuming, Thijs;Newman, Amy Hauck;Weinstein, Hare;Shi, Lei;Loland, Claus J.;Gether, Ulrik
通讯作者：
Gether, Ulrik