Pillar[6]MaxQ: A potent supramolecular host for in vivo sequestration of methamphetamine and fentanyl
Pillar[6]MaxQ: A potent supramolecular host for in vivo sequestration of methamphetamine and fentanyl
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DOI：
10.1016/j.chempr.2022.11.019
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发表时间：
2023-04-13
期刊：
影响因子：
23.5
通讯作者：
Isaacs, Lyle
中科院分区：
文献类型：
--
作者：
Brockett, Adam T.;Xue, Weijian;Isaacs, Lyle
Pillar[6]MaxQ（P6 AS）用作甲基苯丙胺和芬太尼的体内螯合剂。我们使用1H NMR，等温滴定量热法，和分子模拟来推断的P6 AS-药物复合物的几何形状和强度。P6 AS与芬太尼（Kd = 9.8 nM）、PCP（17.1 nM）、MDMA（25.5 nM）、甲氧麻黄酮（52.4 nM）和甲基苯丙胺（101 nM）形成紧密复合物。MTS代谢试验、腺苷酸激酶细胞死亡试验、hERG离子通道抑制试验和艾姆斯波动试验表明，P6 AS具有良好的体外生物相容性。P6 AS的未观察到不良作用水平为45 mg/kg。用甲基苯丙胺（0.5mg/kg）处理的小鼠的过度运动可以通过在5 min后用P6 AS（35.7mg/kg）处理来改善，而用芬太尼（0.1mg/kg）处理的小鼠的过度运动可以通过在15 min后用P6 AS（5 mg/kg）处理来控制。P6 AS作为一种广谱的体内螯合剂具有显著的开发潜力。
Pillar[6]MaxQ (P6AS) functions as an in vivo sequestration agent for methamphetamine and fentanyl. We use 1H NMR, isothermal titration calorimetry, and molecular modeling to deduce the geometry and strength of the P6AS-drug complexes. P6AS forms tight complexes with fentanyl (K-d = 9.8 nM), PCP (17.1 nM), MDMA (25.5 nM), mephedrone (52.4 nM), and methamphetamine (101 nM). P6AS has good in vitro biocompatibility according to MTS metabolic, adenylate kinase cell death, and hERG ion channel inhibition assays, and the Ames fluctuation test. The no observed adverse effect level for P6AS is 45 mg/kg. The hyperlocomotion of mice treated with methamphetamine (0.5 mg/kg) can be ameliorated by treatment with P6AS (35.7 mg/kg) 5 min later, whereas the hyperlocomotion of mice treated with fentanyl (0.1 mg/kg) can be controlled by treatment with P6AS (5 mg/kg) up to 15 min later. P6AS has significant potential for development as a broad-spectrum in vivo sequestration agent.