Fitzgerald Lauren R, Gannon Brenda M, Walther Donna, Landavazo Antonio, Hiranita Takato, Blough Bruce E, Baumann Michael H, Fantegrossi William E
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.
Neuropharmacology. 2024 Mar 1;245:109827. doi: 10.1016/j.neuropharm.2023.109827. Epub 2023 Dec 27.
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众多的苯丙胺类和卡西酮类物质，导致滥用新型精神活性物质的数量不断增加。了解各种取代如何影响苯乙胺的药理学特性，可能有助于立法者和科学家预测新出现药物的效果。在此，我们建立了12种苯乙胺的运动刺激和单胺转运体效应的构效关系，这些苯乙胺具有对氯、β-酮、N-甲基或N-乙基添加物的组合。使用自动光电束分析来评估药物对小鼠活动能力的影响，而体外试验则用于确定大鼠脑突触体中多巴胺（DAT）、去甲肾上腺素（NET）和5-羟色胺（SERT）转运体的活性。在小鼠研究中，除了4-氯-N-乙基卡西酮外，所有化合物均刺激运动。苯丙胺类是比其β-酮类似物更有效的兴奋剂，而对氯苯丙胺往往比未取代的苯丙胺更有效。对氯化合物在其运动剂量-效应函数上升支的剂量下也会产生致死性。体外试验表明，所有化合物均抑制DAT、NET和SERT的摄取，大多数化合物在这些位点也作为底物（即释放剂）起作用。未取代的化合物相对于SERT在DAT和NET上表现出更好的效力。对氯取代或增加N-烷基链长度增强了在SERT上的相对效力，而对氯和N-乙基取代的组合降低了在NET和DAT上的释放作用。这些结果证明了苯乙胺诱导的运动刺激效应、单胺转运体活性和致死性的有序构效关系。重要的是，4-氯化合物在小鼠中产生毒性，这表明在娱乐环境中使用这些药物对人类有严重风险。
