与 CUMYL-PICA、CUMYL-BUTICA、CUMYL-CBMICA 和 CUMYL-PINACA 相关的烷基和脂环族合成大麻素系统文库的综合表征,ACS Chemical Neuroscience

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与 CUMYL-PICA、CUMYL-BUTICA、CUMYL-CBMICA 和 CUMYL-PINACA 相关的烷基和脂环族合成大麻素系统文库的综合表征
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2022-12-18 , DOI: 10.1021/acschemneuro.2c00408
Liesl K Janssens ₁ , Adam Ametovski _{2,

3} , Eric Sparkes _{2,

3} , Rochelle Boyd _{2,

4} , Felcia Lai ₅ , Callan J Maloney _{2,

3} , Dane Rhook _{2,

3} , Roy R Gerona ₆ , Matthew Connolly ₇ , Huiling Liu ₇ , David E Hibbs ₅ , Elizabeth A Cairns _{2,

4} , Samuel D Banister _{2,

3} , Christophe P Stove ₁

Affiliation

超过 200 种合成大麻素受体激动剂 (SCRA) 已被确定为新的精神活性物质。结构演变的快速步伐阻碍了对 SCRA 的有效监测和表征。在可能出现在非法药物市场之前，合成了新的 SCRA 以完成枯基吲哚（例如，CUMYL-CPrMICA、CUMYL-CPMICA）和枯基吲唑甲酰胺（例如, CUMYL-CPrMINACA, CUMYL-CPMINACA)，包括丁基、戊基、环丙基甲基、环丁基甲基、环戊基甲基和环己基甲基尾部。使用三种测定形式进行综合药理学表征，监测野生型或 C 末端截短 (βarr2d366) β-arrestin2 向活化的大麻素 1 受体 (CB ₁ ) 的募集，或监测 G _βγ介导的膜超极化。在比较衍生效力 (EC ₅₀ ) 和功效 ( E _max) 两种检测监测相同或不同信号事件的值，而范围和排序顺序相似。构效关系 (SAR) 进行了三重评估，最终将悬垂尾部鉴定为关键药效团，CB ₁激活的最佳链长接近正戊基（例如，环戊基甲基或环己基甲基尾部）。包含环状尾部的 SCRA 的活性随着形成环状部分的碳数的减少而降低，其中 CUMYL-CPrMICA在所有测定形式中显示出最低的 CB _1活性。SARs 合理化通过分子对接，证明了疏水尾巴的最佳空间贡献的重要性。虽然 SAR 结论基本保持不变，但相似和不同测定设计的差异化合物表征强调了详细说明特定测定特征的重要性，以便充分解释效力和功效。

"点击查看英文标题和摘要"

Comprehensive Characterization of a Systematic Library of Alkyl and Alicyclic Synthetic Cannabinoids Related to CUMYL-PICA, CUMYL-BUTICA, CUMYL-CBMICA, and CUMYL-PINACA

Over 200 synthetic cannabinoid receptor agonists (SCRAs) have been identified as new psychoactive substances. Effective monitoring and characterization of SCRAs are hindered by the rapid pace of structural evolution. Ahead of possible appearance on the illicit drug market, new SCRAs were synthesized to complete a systematic library of cumyl-indole- (e.g., CUMYL-CPrMICA, CUMYL-CPMICA) and cumyl-indazole-carboxamides (e.g., CUMYL-CPrMINACA, CUMYL-CPMINACA), encompassing butyl, pentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl tails. Comprehensive pharmacological characterization was performed with three assay formats, monitoring the recruitment of either wild-type or C-terminally truncated (βarr2d366) β-arrestin2 to the activated cannabinoid 1 receptor (CB₁) or monitoring G_βγ-mediated membrane hyperpolarization. Altered compound characterization was observed when comparing derived potency (EC₅₀) and efficacy (E_max) values from both assays monitoring the same or a different signaling event, whereas ranges and ranking orders were similar. Structure–activity relationships (SAR) were assessed in threefold, resulting in the identification of the pendant tail as a critical pharmacophore, with the optimal chain length for CB₁ activation approximating an n-pentyl (e.g., cyclopentylmethyl or cyclohexylmethyl tail). The activity of the SCRAs encompassing cyclic tails decreased with decreasing number of carbons forming the cyclic moiety, with CUMYL-CPrMICA showing the least CB₁ activity in all assay formats. The SARs were rationalized via molecular docking, demonstrating the importance of the optimal steric contribution of the hydrophobic tail. While SAR conclusions remained largely unchanged, the differential compound characterization by both similar and different assay designs emphasizes the importance of detailing specific assay characteristics to allow adequate interpretation of potencies and efficacies.

更新日期：2022-12-18

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