Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest groups of new psychoactive substances monitored in Europe. SCRAs are known to typically exert higher cannabinoid activity than tetrahydrocannabinol from cannabis, thereby entailing a greater health risk. Both Cumyl‐PEGACLONE and 5F‐Cumyl‐PEGACLONE were not controlled by the national legislation upon their first detection in Germany in 2016 and 2017, respectively, and have been linked to several fatalities. In this study, the CB₁ receptor activity of these compounds, together with two newly synthesized structural isomers (Cumyl‐PEGACLONE ethylbenzyl isomer and n‐propylphenyl isomer), was assessed using two different in vitro receptor‐proximal bioassays, monitoring the recruitment of either β‐arrestin2 (β‐arr2) or a modified G protein (mini‐Gα_i) to the activated CB₁ receptor. In terms of both potency and relative efficacy, Cumyl‐PEGACLONE and 5F‐Cumyl‐PEGACLONE were found to exert strong CB₁ activation, with sub‐nanomolar EC₅₀ values and efficacy values exceeding those of the reference agonist JWH‐018 threefold (β‐arr2 assay) or almost twofold (mini‐Gα_i assay). The ethylbenzyl and n‐propylphenyl isomers exhibited a strongly reduced CB₁ activity (EC₅₀ values >100 nM; efficacy <40% relative to JWH‐018), which is hypothesized to originate from steric hindrance in the ligand‐binding pocket. None of the evaluated compounds exhibited significant biased agonism. In conclusion, the functional assays applied here allowed us to demonstrate that 5‐fluorination of Cumyl‐PEGACLONE is not linked to an intrinsically higher CB₁ activation potential and that the ethylbenzyl and n‐propylphenyl isomers yield a strongly reduced CB₁ activation.

中文翻译：

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Cumyl-PEGACLONE 变体在 CB1 受体上的体外活性分析：氟化与异构体探索。

合成大麻素受体激动剂 (SCRA) 是欧洲监测到的最大的一类新型精神活性物质。众所周知，SCRAs 通常比来自大麻的四氢大麻酚发挥更高的大麻素活性，从而带来更大的健康风险。Cumyl-PEGACLONE 和 5F-Cumyl-PEGACLONE 分别于 2016 年和 2017 年在德国首次被发现时不受国家立法的控制，并且已与多起死亡事件有关。在本研究中，这些化合物的 CB ₁受体活性与两种新合成的结构异构体（Cumyl-PEGACLONE 乙基苄基异构体和正丙基苯基异构体）一起使用两种不同的体外评估受体近端生物测定，监测 β-arrestin2 (β-arr2) 或修饰的 G 蛋白 (mini-Gα _i ) 向激活的 CB ₁受体的募集。在效力和相对功效方面，发现 Cumyl-PEGACLONE 和 5F-Cumyl-PEGACLONE 具有很强的 CB ₁活化作用，EC ₅₀值和功效值超过参考激动剂 JWH-018 的三倍（β- arr2 测定）或几乎两倍（mini-Gα _i测定）。乙基苄基和正丙基苯基异构体表现出强烈降低的 CB ₁活性（EC ₅₀值 > 100 nM；相对于 JWH-018 的疗效 <40%），假设其源于配体结合口袋中的空间位阻。所评估的化合物均未表现出显着的偏向激动作用。总之，这里应用的功能测定使我们能够证明 Cumyl-PEGACLONE 的 5-氟化与固有的更高 CB ₁活化潜力无关，并且乙基苄基和正丙基苯基异构体产生强烈降低的 CB ₁活化。