The emergence of new synthetic cannabinoid receptor agonists (SCRAs) onto the illicit drugs market continues to cause harm, and the overall availability of physicochemical and pharmacokinetic data for new psychoactive substances is lacking. The lipophilicity of 23 SCRAs and the plasma protein binding (PPB) of 11 SCRAs was determined. Lipophilicity was determined using a validated chromatographic hydrophobicity index (CHI) log D method; tested SCRAs showed moderate to high lipophilicity, with experimental log D_7.4 ranging from 2.48 (AB-FUBINACA) to 4.95 (4F-ABUTINACA). These results were also compared to in silico predictions generated using seven commercially available software packages and online tools (Canvas; ChemDraw; Gastroplus; MoKa; PreADMET; SwissADME; and XlogP). Licenced, dedicated software packages provided more accurate lipophilicity predictions than those which were free or had prediction as a secondary function; however, the latter still provided competitive estimates in most cases. PPB of tested SCRAs, as determined by equilibrium dialysis, was in the upper range of the lipophilicity scale, ranging from 90.8% (ADB-BUTINACA) to 99.9% (BZO-HEXOXIZID). The high PPB of these drugs may contribute to reduced rate of clearance and extended durations of pharmacological effects compared to lesser-bound SCRAs. The presented data improve understanding of the behaviour of these drugs in the body. Ultimately, similar data and predictions may be used in the prediction of the structure and properties of drugs yet to emerge on the illicit market.

中文翻译：

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Log D7.4 和合成大麻素受体激动剂的血浆蛋白结合以及实验和预测亲脂性的比较

非法药物市场上出现的新型合成大麻素受体激动剂（SCRA）继续造成危害，并且缺乏新型精神活性物质的物理化学和药代动力学数据的整体可用性。测定了 23 种 SCRA 的亲脂性和 11 种 SCRA 的血浆蛋白结合 (PPB)。使用经过验证的色谱疏水性指数 (CHI) log D 方法测定亲脂性；测试的 SCRA 显示出中度至高度的亲脂性，实验 log D _7.4范围为 2.48 (AB-FUBINACA) 至 4.95 (4F-ABUTINACA)。这些结果还与使用七个商用软件包和在线工具（Canvas、ChemDraw、Gastroplus、MoKa、PreADMET、SwissADME 和 XlogP）生成的计算机预测进行了比较。获得许可的专用软件包比免费软件包或将预测作为次要功能的软件包提供更准确的亲脂性预测；然而，后者在大多数情况下仍然提供了有竞争力的估计。通过平衡透析测定，测试 SCRA 的 PPB 处于亲脂性范围的上限，范围从 90.8% (ADB-BUTINACA) 到 99.9% (BZO-HEXOXIZID)。与结合较少的 SCRA 相比，这些药物的高 PPB 可能有助于降低清除率并延长药理作用的持续时间。所提供的数据增进了对这些药物在体内行为的理解。最终，类似的数据和预测可用于预测非法市场上尚未出现的药物的结构和特性。