新精神活性物质(NPS)的前景在不断发展,随着新化合物不断进入非法药物市场。其中,阿片类NPS由于其高效能和患病率而构成威胁。而以前,芬太尼和芬太尼衍生物的使用是主要的关注点,立法已经做出了相应的反应,这可能是(ab)使用替代µ阿片受体(MOR)激动剂的驱动力。与芬太尼(类似物)相比,有关这些新型非芬太尼阿片类NPS的详细信息尚不清楚.我们调查了一组11个“替代品”的生物活性,新出现的MOR激动剂(2-甲基-AP-237,AP-237,溴,Brorphine,布托啡诺,异硝基苯,mitragynine,7-OH-mitragynine,MT-45,哌啶基硫代丁烯,和tianeptine)使用两个密切相关的体外MOR激活生物测定,监测G蛋白(mini-Gi),或β-arrestin2(βarr2)募集。获得了所有测试化合物的活性概况,效力值(EC50)范围为1.89nM(溴马多)至>3µM(AP-237和tianeptine)。Bromadol,Brorphine,异硝基苯,哌啶基硫代丁烯,tianeptine具有最高的疗效(Emax)值,超过参考化合物氢吗啡酮≥1.3倍(βarr2测定)和>2.6倍(mini-Gi测定)。关于两种不同的信号分子的募集的信息另外使得能够评估有偏倚的激动作用;所评估的阿片样物质中没有一个是显著有偏倚的。一起来看,这项研究首次系统地研究了MOR中出现的各种非芬太尼阿片类NPS的体外生物学活性。鉴于已知许多阿片类NPS(致命)中毒的危险,重要的是不断监测和表征新出现的化合物。
The landscape of new psychoactive substances (NPS) is constantly evolving, with new compounds entering the illicit drug market at a continuous pace. Of these, opioid NPS form a threat given their high potency and prevalence. Whereas previously, the use of fentanyl and fentanyl derivatives was the main point of attention, legislations have reacted accordingly, which may have been a driving force towards the (ab)use of alternative µ-opioid receptor (MOR) agonists. In contrast to fentanyl (analogues), details on these novel non-fentanyl opioid NPS are scarce. We investigated the biological activity of a panel of 11 \'alternative\', newly emerging MOR agonists (2-methyl-AP-237, AP-237, bromadol, brorphine, butorphanol, isotonitazene, mitragynine, 7-OH-mitragynine, MT-45, piperidylthiambutene, and tianeptine) using two closely related in vitro MOR activation bio-assays, monitoring either G protein (mini-Gi), or β-arrestin2 (βarr2) recruitment. Activity profiles were obtained for all tested compounds, with values for potency (EC50) ranging from 1.89 nM (bromadol) to > 3 µM (AP-237 and tianeptine). Bromadol, brorphine, isotonitazene, piperidylthiambutene, and tianeptine had the highest efficacy (Emax) values, exceeding that of the reference compound hydromorphone ≥ 1.3-fold (βarr2 assay) and > 2.6-fold (mini-Gi assay). Information on the recruitment of two distinct signaling molecules additionally enabled evaluation of biased agonism; none of the evaluated opioids being significantly biased. Taken together, this study is the first to systematically investigate the in vitro biological activity of a diverse panel of emerging non-fentanyl opioid NPS at MOR. Given the known danger of (fatal) intoxications with many opioid NPS, it is important to continuously monitor and characterize newly emerging compounds.