Kolanos R, Sakloth F, Jain A D, Partilla J S, Baumann M H, Glennon R A
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , 800 East Leigh Street, PO Box 980540, Richmond, Virginia 23298, United States.
Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health , Baltimore, Maryland 21224, United States.
ACS Chem Neurosci. 2015 Oct 21;6(10):1726-31. doi: 10.1021/acschemneuro.5b00160. Epub 2015 Aug 11.
α-Pyrrolidinovalerophenone (α-PVP, 7) is an illegal synthetic stimulant that is being sold on the clandestine market as "flakka" and "gravel". The potent pharmacological effects of α-PVP are presumably mediated by inhibition of dopamine uptake at the dopamine transporter (DAT). However, little is known about how structural modification of α-PVP influences activity at DAT. Eleven analogs of α-PVP were synthesized and examined for their ability to inhibit uptake of [(3)H]dopamine and [(3)H]serotonin in rat brain synaptosomes. None of the analogs significantly inhibited [(3)H]serotonin uptake when tested at 10 μM at the serotonin transporter (SERT). All of the analogs behaved as DAT reuptake inhibitors, but potencies varied over a >1500-fold range. Potency was primarily associated with the nature of the α-substituent, with the more bulky substituents imparting the highest potency. Expansion of the pyrrolidine ring to a piperidine reduced potency up to 10-fold, whereas conformational constraint in the form of an aminotetralone resulted in the least potent compound. Our study provides the first systematic and comparative structure-activity investigation on the ability of α-PVP analogs to act as inhibitors of DAT.
α-吡咯烷戊酮（α-PVP，7）是一种非法合成兴奋剂，在地下市场上作为“弗拉卡”和“砾石”出售。α-PVP的强效药理作用可能是通过抑制多巴胺转运体（DAT）上的多巴胺摄取来介导的。然而，关于α-PVP的结构修饰如何影响DAT活性知之甚少。合成了11种α-PVP类似物，并检测了它们抑制大鼠脑突触体中[³H]多巴胺和[³H]5-羟色胺摄取的能力。在5-羟色胺转运体（SERT）上以10 μM进行测试时，没有一种类似物能显著抑制[³H]5-羟色胺的摄取。所有类似物均表现为DAT再摄取抑制剂，但效力在超过1500倍的范围内变化。效力主要与α-取代基的性质有关，取代基体积越大，效力越高。将吡咯烷环扩展为哌啶会使效力降低多达10倍，而以氨基四氢萘酮形式存在的构象限制导致效力最低的化合物。我们的研究首次对α-PVP类似物作为DAT抑制剂的能力进行了系统的比较构效关系研究。
