Despite synthetic cannabinoids' (SCs) prevalent use among humans, these substances often lack comprehensive pharmacological data, primarily due to their rapid emergence in the market. This study aimed to discern differences and causal factors among four SCs (ADB-BICA, ADB-BINACA, ADB-4en-PINACA and MDMB-4en-PINACA), with respect to locomotor activity, body temperature and nociception threshold. Adult male C57BL/6 mice received intraperitoneal injections of varying doses (0.5, 0.1 and 0.02 mg/kg) of these compounds. Three substances (including ADB-BINACA, ADB-4en-PINACA and MDMB-4en-PINACA) demonstrated dose- and time-dependent hypolocomotive and hypothermic effects. Notably, 0.1 mg/kg MDMB-4en-PINACA exhibited analgesic properties. However, ADB-BICA did not cause any effects. MDMB-4en-PINACA manifested the most potent and sustained effects, followed by ADB-4en-PINACA, ADB-BINACA and ADB-BICA. Additionally, the cannabinoid receptor 1 (CB1R) antagonist AM251 suppressed the effects induced by acute administration of the substances. Analysis of molecular binding configurations revealed that the four SCs adopted a congruent C-shaped geometry, with shared linker binding pockets conducive to robust steric interaction with CB1R. Essential residues PHE²⁶⁸, PHE²⁰⁰ and SER¹⁷³ within CB1R were identified as pivotal contributors to enhancing receptor–ligand associations. During LC-MS/MS analysis, 0.5 mg/kg MDMB-4en-PINACA exhibited the highest plasma concentration and most prolonged detection window post-administration. The study of SCs' pharmacological and pharmacokinetic profiles is crucial for better understanding the main mechanisms of cannabinoid-like effects induced by SCs, interpreting clinical findings related to SC uses and enhancing SCs risk awareness.

中文翻译：

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ADB-BICA、ADB-BINACA、ADB-4en-PINACA 和 MDMB-4en-PINACA 在小鼠体内的差异大麻素样作用和药代动力学：比较研究


尽管合成大麻素（SC）在人类中普遍使用，但这些物质往往缺乏全面的药理学数据，这主要是由于它们在市场上的迅速出现。本研究旨在辨别四种 SC（ADB-BICA、ADB-BINACA、ADB-4en-PINACA 和 MDMB-4en-PINACA）在运动活动、体温和伤害感受阈值方面的差异和因果因素。成年雄性 C57BL/6 小鼠腹膜内注射不同剂量（0.5、0.1 和 0.02 mg/kg）的这些化合物。三种物质（包括 ADB-BINACA、ADB-4en-PINACA 和 MDMB-4en-PINACA）表现出剂量和时间依赖性的运动减退和体温降低效应。值得注意的是，0.1 mg/kg MDMB-4en-PINACA 表现出镇痛特性。然而，ADB-BICA 并未造成任何影响。 MDMB-4en-PINACA 表现出最有效和持续的效果，其次是 ADB-4en-PINACA、ADB-BINACA 和 ADB-BICA。此外，大麻素受体 1 (CB1R) 拮抗剂 AM251 抑制了急性给药引起的效应。分子结合构型分析表明，四个 SC 采用全等的 C 形几何形状，具有共享的接头结合口袋，有利于与 CB1R 的稳健空间相互作用。 CB1R 内的必需残基 PHE ²⁶⁸ 、 PHE ²⁰⁰和 SER ¹⁷³被确定为增强受体-配体结合的关键贡献者。在 LC-MS/MS 分析过程中，0.5 mg/kg MDMB-4en-PINACA 表现出最高的血浆浓度和最长的给药后检测窗。 SC 的药理学和药代动力学特征的研究对于更好地了解 SC 引起的大麻素样作用的主要机制、解释与 SC 使用相关的临床结果以及提高 SC 风险意识至关重要。