Smith Douglas A, Blough Bruce E, Banks Matthew L
Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th St., PO Box 980613, Richmond, VA, 23298, USA.
Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, USA.
Psychopharmacology (Berl). 2017 Jan;234(1):117-127. doi: 10.1007/s00213-016-4444-1. Epub 2016 Oct 5.
Synthetic cathinones have emerged as the newest class of abused monoamine transporter substrates. Structurally, these compounds are all beta-ketone amphetamine (cathinone) analogs. Whether synthetic cathinone analogs produce differential behavioral effects from their amphetamine analog counterparts has not been systematically examined. Preclinical drug discrimination procedures have been useful for determining the structure activity relationships (SARs) of abused drugs; however, direct comparisons between amphetamine and cathinone analogs are lacking and, in particular, in non-human primate models.
The study aim was to determine the potency and time course of (±)-amphetamine, (±)-cathinone, and (±)-methamphetamine and their 3,4-methylenedioxy analogs (±)-MDA, (±)-MDC, and (±)-MDMA, respectively, to produce cocaine-like discriminative stimulus effects. If cathinone analogs have similar behavioral pharmacological properties to their amphetamine counterparts, then we would predict similar potencies and efficacies to produce cocaine-like discriminative stimulus effects.
Male rhesus monkeys (n = 4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure.
Racemic amphetamine, cathinone, and methamphetamine produced dose-dependent and full substitution, ≥90 % cocaine-appropriate responding, in all monkeys. Addition of 3,4-methylenedioxy moiety attenuated both the potency and efficacy of amphetamine (MDA), cathinone (MDC), and methamphetamine (MDMA) to produce full cocaine-like effects. Moreover, the cocaine-like effects of amphetamine and cathinone were attenuated to a greater extent than those of methamphetamine or previously published methcathinone (Smith et al. 2016).
The presence of an N-methyl group blunted both the potency and the efficacy shift of the 3,4-methylenedioxy addition for both amphetamine and cathinone analogs.
合成卡西酮已成为最新一类被滥用的单胺转运体底物。从结构上看，这些化合物都是β-酮苯丙胺（卡西酮）类似物。合成卡西酮类似物与其苯丙胺类似物对应物是否产生不同的行为效应尚未得到系统研究。临床前药物辨别程序对于确定被滥用药物的构效关系（SARs）很有用；然而，缺乏苯丙胺和卡西酮类似物之间的直接比较，尤其是在非人类灵长类动物模型中。
本研究旨在分别确定（±）-苯丙胺、（±）-卡西酮、（±）-甲基苯丙胺及其3,4-亚甲二氧基类似物（±）-MDA、（±）-MDC和（±）-MDMA产生可卡因样辨别刺激效应的效力和时程。如果卡西酮类似物与其苯丙胺对应物具有相似的行为药理学特性，那么我们可以预测它们产生可卡因样辨别刺激效应的效力和效能相似。
雄性恒河猴（n = 4）在双按键食物强化辨别程序中接受训练，以区分肌肉注射的可卡因（0.32 mg/kg）和生理盐水。
外消旋苯丙胺、卡西酮和甲基苯丙胺在所有猴子中均产生剂量依赖性和完全替代作用，即≥90%的可卡因适宜反应。添加3,4-亚甲二氧基部分会减弱苯丙胺（MDA）、卡西酮（MDC）和甲基苯丙胺（MDMA）产生完全可卡因样效应的效力和效能。此外，苯丙胺和卡西酮的可卡因样效应比甲基苯丙胺或先前发表的去甲伪麻黄碱（Smith等人，2016年）的效应减弱程度更大。
对于苯丙胺和卡西酮类似物，N-甲基的存在使3,4-亚甲二氧基添加导致的效力和效能变化均减弱。
