The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue.
The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue.
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DOI：
10.1016/j.neuropharm.2015.09.004
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发表时间：
2016-02
影响因子：
4.7
通讯作者：
Baumann MH
中科院分区：
文献类型：
--
作者：
Marusich JA;Antonazzo KR;Blough BE;Brandt SD;Kavanagh PV;Partilla JS;Baumann MH
近年来，精神活性合成兴奋剂的使用迅速增长。5-(2-氨基丙基)吲哚(5-IT)是一种与多种死亡有关的合成药物，似乎是最新的3，4-亚甲基二氧甲基苯丙胺(MDMA)替代品之一。本文采用大鼠脑突触体内多巴胺(DAT)、去甲肾上腺素(NET)和5-羟色胺(SERT)转运体的体外释放实验，比较了5-IT及其结构异构体6-(2-氨基丙基)吲哚(6-IT)和MDMA的单胺释放特性。体内药理通过小鼠的运动活动和功能观察电池(FOB)进行评估。5-IT和6-IT是DAT、NET和SERT的有效底物。与MDMA的非选择性释放特性相比，5-IT在DAT时的释药效率高于SERT，而6-IT在SERT时的释药效率高于DAT。5-IT在FOB产生与MDMA相似的运动刺激和典型的刺激效应。相反，6-IT增加了与5-HT毒性相关的行为。5-IT可能具有很高的滥用潜力，这种潜力可能会因其缓慢的体内效应而有所减弱，而6-IT可能具有较低的滥用倾向，但增加了不良影响的风险。结果表明，转运蛋白配体的化学结构的细微差异可以对生物活性产生深远的影响。5-IT强大的单胺释放作用，加上已知的对MAO A的抑制，可能是单独给药以及与其他单胺类药物或药物联合使用时的危险作用。因此，5-IT和相关化合物可能会对人类使用者造成滥用和严重不良影响的重大风险。
In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users.