Substitutions to the phenethylamine structure give rise to numerous amphetamines and cathinones, contributing to an ever-growing number of abused novel psychoactive substances. Understanding how various substitutions affect the pharmacology of phenethylamines may help lawmakers and scientists predict the effects of newly emerging drugs. Here, we established structure-activity relationships for locomotor stimulant and monoamine transporter effects of 12 phenethylamines with combinations of para-chloro, β-keto, N-methyl, or N-ethyl additions. Automated photobeam analysis was used to evaluate effects of drugs on ambulatory activity in mice, whereas in vitro assays were used to determine activities at transporters for dopamine (DAT), norepinephrine (NET), and 5-HT (SERT) in rat brain synaptosomes. In mouse studies, all compounds stimulated locomotion, except for 4-chloro-N-ethylcathinone. Amphetamines were more potent stimulants than their β-keto counterparts, while para-chloro amphetamines tended to be more efficacious than unsubstituted amphetamines. Para-chloro compounds also produced lethality at doses on the ascending limbs of their locomotor dose-effect functions. The in vitro assays showed that all compounds inhibited uptake at DAT, NET, and SERT, with most compounds also acting as substrates (i.e., releasers) at these sites. Unsubstituted compounds displayed better potency at DAT and NET relative to SERT. Para-chloro substitution or increased N-alkyl chain length augmented relative potency at SERT, while combined para-chloro and N-ethyl substitutions reduced releasing effects at NET and DAT. These results demonstrate orderly SAR for locomotor stimulant effects, monoamine transporter activities, and lethality induced by phenethylamines. Importantly, 4-chloro compounds produce toxicity in mice that suggests serious risk to humans using these drugs in recreational contexts.

苯乙胺结构的取代产生了大量的安非他明和卡西酮，导致滥用的新型精神活性物质的数量不断增加。了解各种替代品如何影响苯乙胺的药理学可能有助于立法者和科学家预测新兴药物的作用。在这里，我们建立了12 种苯乙胺与对氯、β-酮、N-甲基或 N-乙基加成物组合的运动兴奋剂和单胺转运蛋白效应的结构-活性关系。自动光束分析用于评估药物对小鼠行走活动的影响，而体外测定用于确定大鼠脑突触体中多巴胺 (DAT)、去甲肾上腺素 (NET) 和 5-HT (SERT) 转运蛋白的活性。在小鼠研究中，除 4-氯-N-乙基卡西酮外，所有化合物均刺激运动。安非他明是比β-酮类药物更有效的兴奋剂，而对氯安非他明往往比未取代的安非他明更有效。对氯化合物在其运动剂量效应函数的上升肢的剂量下也产生致死率。体外测定表明，所有化合物均抑制 DAT、 NET大多数化合物还在这些位点充当底物（即释放剂）。相对于 SERT，未取代的化合物在 DAT 和 NET 方面表现出更好的效力。对氯取代或增加的N-烷基链长度增强了 SERT 的相对效力，而组合的对氯和N-乙基取代降低了 NET 和 DAT 的释放效果。这些结果表明，苯乙胺诱导的运动刺激作用、单胺转运蛋白活性和致死率具有有序的 SAR。重要的是，4-氯化合物会对小鼠产生毒性，这表明人类在娱乐环境中使用这些药物存在严重风险。