Application of an activity-based receptor bioassay to investigate the in vitro activity of selected indole- and indazole-3-carboxamide-based synthetic cannabinoids at CB1 and CB2 receptors
Application of an activity-based receptor bioassay to investigate the in vitro activity of selected indole- and indazole-3-carboxamide-based synthetic cannabinoids at CB1 and CB2 receptors
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DOI：
10.1002/dta.2517
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发表时间：
2019-03-01
影响因子：
2.9
通讯作者：
Stove, Christophe P.
中科院分区：
文献类型：
--
作者：
Noble, Carolina;Cannaert, Annelies;Stove, Christophe P.
合成大麻素（SC）是化学上最多样化的一类新的精神活性物质。这个群体与几种中毒有关，许多都有致命的后果。尽管近年来这些化合物在药理学、代谢和检测方面取得了进展，但许多SC的这些方面仍然没有得到解决。本研究的目的是通过应用稳定的CB 1或CB 2受体活化试验并将活性与其结构相关联来研究14种基于吲哚和吲唑的SC的体外效力。5-氯戊基、5-溴戊基和5-碘戊基JWH-122类似物的半数最大有效浓度（EC 50）在CB 1的74.1至283.7 nM和CB 2的7.05至23.4 nM之间变化，其中与溴和碘类似物相比，添加氯原子增强了CB 1的效力。AM-2201在该萘酰吲哚家族中对CB 1的活性最高，EC 50为23.5 nM，但效力最低（E-max 98.8%）。在吲哚-3-甲酰胺衍生物中，5 F-MDMB-PICA是活性最高的化合物，CB 1/CB 2 EC 50为3.26/0.87 nM，E-max约为JWH-018的三倍。总体而言，ADB-FUBINACA是最有效的测试SC，CB 1/CB 2 EC 50为0.69/0.59 nM，在CB 1处的E-max约为JWH-018的3倍。这项研究中获得的数据证实了SC结构的微小差异可能导致其活性的巨大差异，特别是在CB 1，这可能与其对人类的毒性作用差异有关。
Synthetic cannabinoids (SCs) are the most chemically diverse group of new psychoactive substances. This group has been associated with several intoxications, many with fatal outcomes. Although advancements have been achieved in pharmacology, metabolism, and detection of these compounds in recent years, these aspects are still unresolved for many SCs. The aim of this study was to investigate the in vitro potency of 14 indole- and indazole-based SCs by applying a stable CB1 or CB2 receptor activation assay and correlating the activity with their structure. The half-maximal effective concentration (EC50) of 5-chloropentyl, 5-bromopentyl, and 5-iodopentyl JWH-122 analogs varied from 74.1 to 283.7 nM for CB1 and 7.05 to 23.4 nM for CB2, where the addition of a chlorine atom enhanced the potency at CB1 compared with the bromo and iodo analogs. AM-2201 was the most active at CB1 within this naphthoylindole family, with an EC50 of 23.5 nM but with the lowest efficacy (E-max 98.8%). Within the indole-3-carboxamide derivatives, 5F-MDMB-PICA was the most active compound, with a CB1/CB2 EC50 of 3.26/0.87 nM and an E-max around three times higher than JWH-018. ADB-FUBINACA was the most potent tested SC overall, with a CB1/CB2 EC50 of 0.69/0.59 nM, and an E-max around 3-fold higher than that for JWH-018 at CB1. The data obtained in this study confirm how small differences in the structure of SCs might lead to large differences in their activity, especially at CB1, which may be correlated with differences in their toxic effects in humans.