School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, L3 3AF, Liverpool, UK.
Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Suite 4400, Baltimore, MD, 21224, USA.
Psychopharmacology (Berl). 2020 Dec;237(12):3703-3714. doi: 10.1007/s00213-020-05648-z. Epub 2020 Sep 1.
The nonmedical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called "benzofury" compounds, 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models.
Here, we used in vitro monoamine transporter assays in rat brain synaptosomes to characterize the effects of 5-APB and 6-APB, together with their N-methyl derivatives 5-MAPB and 6-MAPB, in comparison with 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA). In vivo neurochemical and behavioral effects of 5-APB (0.3 and 1.0 mg/kg, i.v.) and 6-APB (0.3 and 1.0 mg/kg, i.v.) were assessed in comparison with MDA (1.0 and 3.0 mg/kg, i.v.) using microdialysis sampling in the nucleus accumbens of conscious male rats.
All four benzofuran derivatives were substrate-type releasers at dopamine transporters (DAT), norepinephrine transporters (NET), and serotonin transporters (SERT) with nanomolar potencies, similar to the profile of effects produced by MDA and MDMA. However, the benzofurans were at least threefold more potent than MDA and MDMA at evoking transporter-mediated release. Like MDA, both benzofurans induced dose-related elevations in extracellular dopamine and serotonin in the brain, but benzofurans were more potent than MDA. The benzofuran derivatives also induced profound behavioral activation characterized by forward locomotion which lasted for at least 2 h post-injection.
Overall, benzofurans are more potent than MDA in vitro and in vivo, producing sustained stimulant-like effects in rats. These data suggest that benzofuran-type compounds may have abuse liability and could pose risks for adverse effects, especially if used in conjunction with abused drugs or medications which enhance monoamine transmission in the brain.
新精神活性物质（NPS）的非医疗用途是全球公共卫生关注的一个问题。所谓的“苯并呋喃”化合物，5-(2-氨基丙基)苯并呋喃（5-APB）和 6-(2-氨基丙基)苯并呋喃（6-APB），是人类使用者具有刺激特性的 NPS。这些物质已知会与转染细胞中的单胺转运体和 5-HT 受体相互作用，但对它们在动物模型中的作用知之甚少。
在这里，我们使用大鼠脑突触体中的体外单胺转运体测定法，来描述 5-APB 和 6-APB 及其 N-甲基衍生物 5-MAPB 和 6-MAPB 与 3,4-亚甲二氧基苯丙胺（MDA）和 3,4-亚甲二氧基甲基苯丙胺（MDMA）的作用，与 5-APB（0.3 和 1.0mg/kg，iv）和 6-APB（0.3 和 1.0mg/kg，iv）在体内神经化学和行为效应进行了比较，使用清醒雄性大鼠伏隔核中的微透析采样。
所有四种苯并呋喃衍生物均为多巴胺转运体（DAT）、去甲肾上腺素转运体（NET）和 5-羟色胺转运体（SERT）的底物型释放剂，具有纳摩尔效力，与 MDA 和 MDMA 产生的作用相似。然而，苯并呋喃类化合物在引发转运体介导的释放方面的效力至少比 MDA 和 MDMA 高三倍。与 MDA 一样，两种苯并呋喃都诱导了与剂量相关的脑外多巴胺和 5-羟色胺的升高，但苯并呋喃比 MDA 更有效。苯并呋喃衍生物还诱导了深刻的行为激活，表现为向前运动，至少持续 2 小时注射后。
总的来说，苯并呋喃类化合物在体外和体内比 MDA 更有效，在大鼠中产生持续的刺激样作用。这些数据表明，苯并呋喃类化合物可能具有滥用潜力，并可能带来不良影响的风险，特别是如果与大脑中增强单胺传递的滥用药物或药物一起使用。
