Grafinger Katharina Elisabeth, Cannaert Annelies, Ametovski Adam, Sparkes Eric, Cairns Elizabeth, Banister Samuel D, Auwärter Volker, Stove Christophe P
Laboratory of Toxicology Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Institute of Forensic Medicine, Forensic Toxicology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Drug Test Anal. 2021 Jul;13(7):1402-1411. doi: 10.1002/dta.3035. Epub 2021 Apr 14.
Synthetic cannabinoid receptor agonists (SCRAs) are the second largest class of new psychoactive substances (NPS) and are associated with serious adverse effects and even death. Despite this, little pharmacological data are available for many of the most recent SCRAs. This study consists of three different parts, aiming to systematically evaluate a panel of 30 SCRAs using binding and different in vitro human cannabinoid 1 receptor (CB ) activation assays. The present Part II investigated the SCRA analogs for their CB activation via a β-arrestin recruitment assay. The panel was systematically designed to include key structural sub-features of recent SCRAs. Thus, the 4-pentenyl tail of MMB-4en-PICA and MDMB-4en-PINACA was retained while incorporating varying head groups from other prevalent SCRAs, including amides and esters of L-valine, L-tert-leucine, and L-phenylalanine, and adamantyl and cumyl moieties. All 30 SCRAs activated CB , with indazoles generally showing the greatest potency (EC = 1.88-281 nM), followed by indoles (EC = 11.5-2293 nM), and the corresponding 7-azaindoles (EC = 62.4-9251 nM). Several subunit-linked structure-activity relationships were identified: (i) tert-leucine-functionalized SCRAs were more potent than the corresponding valine derivatives; (ii) no major difference in potency or efficacy was observed between tert-leucine/valine-derived amides and the corresponding methyl esters; however, phenylalanine analogs were affected by this change; and (iii) minor structural changes to the 4-pentenyl substituent had little influence on activity. These findings elucidate structural features that modulate the CB activation potential of currently prevalent SCRAs and a systematic panel of analogs, some of which may appear in NPS markets in future.
合成大麻素受体激动剂（SCRAs）是新型精神活性物质（NPS）的第二大类，与严重不良反应甚至死亡有关。尽管如此，许多最新的SCRAs的药理学数据却很少。本研究由三个不同部分组成，旨在通过结合和不同的体外人大麻素1受体（CB）激活试验，系统评估一组30种SCRAs。本第二部分通过β-抑制蛋白募集试验研究了SCRAs类似物的CB激活情况。该组化合物经过系统设计，纳入了近期SCRAs的关键结构子特征。因此，保留了MMB-4en-PICA和MDMB-4en-PINACA的4-戊烯基尾部，同时引入了其他常见SCRAs的不同头部基团，包括L-缬氨酸、L-叔亮氨酸和L-苯丙氨酸的酰胺和酯，以及金刚烷基和苄基部分。所有30种SCRAs均激活了CB，吲唑类化合物通常显示出最大的效力（EC50 = 1.88 - 281 nM），其次是吲哚类（EC50 = 11.5 - 2293 nM），以及相应的7-氮杂吲哚类（EC50 = 62.4 - 9251 nM）。确定了几个与亚基相关的构效关系：（i）叔亮氨酸功能化的SCRAs比相应的缬氨酸衍生物更有效；（ii）叔亮氨酸/缬氨酸衍生的酰胺与相应的甲酯在效力或效能上未观察到重大差异；然而，苯丙氨酸类似物受此变化影响；（iii）4-戊烯基取代基的微小结构变化对活性影响不大。这些发现阐明了调节当前流行的SCRAs和一组系统类似物CB激活潜力的结构特征，其中一些未来可能会出现在NPS市场中。
