Department of Psychology and Program in Neuroscience and Cognitive Science (NACS), University of Maryland at College Park, College Park, MD 20742, United States.
Department of Chemistry and Biochemistry, University of Maryland at College Park, College Park, MD 20742, United States.
Chemistry. 2021 Dec 9;27(69):17476-17486. doi: 10.1002/chem.202102919. Epub 2021 Oct 27.
We report the synthesis of two new acyclic sulfated acyclic CB[n]-type receptors (TriM0 and Me TetM0) and investigations of their binding properties toward a panel of drugs of abuse (1-13) by a combination of H NMR spectroscopy and isothermal titration calorimetry. TetM0 is the most potent receptor with K ≥10 M toward methamphetamine, fentanyl, MDMA and mephedrone. TetM0 is not cytotoxic toward HepG2 and HEK 293 cells below 100 μM according to MTS metabolic and adenylate kinase release assays and is well tolerated in vivo when dosed at 46 mg kg . TetM0 does not inhibit the hERG ion channel and is not mutagenic based on the Ames fluctuation test. Finally, in vivo efficacy studies show that the hyperlocomotion of mice treated with methamphetamine can be greatly reduced by treatment with TetM0 up to 5 minutes later. TetM0 has potential as a broad spectrum in vivo sequestrant for drugs of abuse.
我们报告了两种新的非循环磺酸非循环 CB[n]型受体（TriM0 和 Me TetM0）的合成，并通过 1 H NMR 光谱和等温滴定量热法组合研究了它们对一系列滥用药物（1-13）的结合特性。TetM0 是对甲基苯丙胺、芬太尼、MDMA 和苯丙胺最有效的受体，K 值≥10 M。根据 MTS 代谢和腺苷酸激酶释放测定，TetM0 在低于 100 μM 时对 HepG2 和 HEK 293 细胞没有细胞毒性，并且在 46 mg/kg 剂量下在体内耐受良好。TetM0 不抑制 hERG 离子通道，根据 Ames 波动试验也没有致突变性。最后，体内疗效研究表明，用 TetM0 治疗后，用甲基苯丙胺处理的小鼠的过度运动可以大大减少，甚至在 5 分钟后也能减少。TetM0 有望成为一种广谱的滥用药物体内隔离剂。
