Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institute of Biomedicine (IBUB), Faculty of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain.
Pharmaceutical Chemistry Group (GQF), IQS School of Engineering, Universitat Ramon Llull, 08017 Barcelona, Spain.
Int J Mol Sci. 2022 Feb 17;23(4):2226. doi: 10.3390/ijms23042226.
Changes in the molecular structure of synthetic cathinones has led to an increase in the number of novel emerging drugs in the illicit drug market at an unprecedented rate. Unfortunately, little is known about the neuropsychopharmacology of recently emerged halogen-substituted α-PVP derivatives. Thus, the aim of this study was to investigate the role of - and -halogen (F-, Cl-, and Br-) substitutions on the in vitro, in silico, and in vivo effects of α-pyrrolidinopentiophenone (α-PVP) derivatives. HEK293 cells expressing the human dopamine or serotonin transporter (hDAT and hSERT) were used for the uptake inhibition and transporter affinity assays. Molecular docking was used to model the interaction mechanism against DAT. Swiss CD-1 mice were used for the horizontal locomotor activity, open field test, and conditioned place preference paradigm. All compounds demonstrated potent DA uptake inhibition and higher DAT selectivity than cocaine. -substituted cathinones showed higher DAT/SERT ratios than their - analogs, which correlates with an increased psychostimulant effect in vivo and with different - and -in silico interactions at DAT. Moreover, all compounds induced rewarding and acute anxiogenic effects in mice. In conclusion, the present study demonstrates the role of - and -halogen substitutions in the mechanism of action and provides the first evidence of the rewarding and anxiety-like properties of halogenated α-PVP derivatives.
合成卡西酮的分子结构发生变化，导致非法毒品市场中新出现的新型药物数量以前所未有的速度增加。不幸的是，人们对最近出现的卤素取代的 α-PVP 衍生物的神经精神药理学知之甚少。因此，本研究旨在探讨 - 和 - 卤素（F-、Cl- 和 Br-）取代对 α-吡咯烷酮戊基酮（α-PVP）衍生物的体外、计算和体内作用的影响。表达人多巴胺或血清素转运体（hDAT 和 hSERT）的 HEK293 细胞用于摄取抑制和转运体亲和力测定。分子对接用于模拟与 DAT 的相互作用机制。瑞士 CD-1 小鼠用于水平运动活动、旷场试验和条件性位置偏好范式。所有化合物均表现出强烈的 DA 摄取抑制作用和比可卡因更高的 DAT 选择性。- 取代的卡西酮比其 - 类似物具有更高的 DAT/SERT 比值，这与体内更强的精神兴奋剂作用以及 DAT 上不同的 - 和 - 计算相互作用相关。此外，所有化合物在小鼠中均诱导产生奖赏和急性焦虑样作用。总之，本研究证明了 - 和 - 卤素取代在作用机制中的作用，并首次提供了卤代 α-PVP 衍生物具有奖赏和焦虑样特性的证据。
