葫芦[8]脲对苯环利定的体外和体内螯合作用*。
In Vitro and In Vivo Sequestration of Phencyclidine by Me Cucurbit[8]uril*.
机构信息
Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, 20742, USA.
Department of Psychology, University of Maryland, College Park, MD, 20742, USA.
出版信息
Chemistry. 2021 Feb 10;27(9):3098-3105. doi: 10.1002/chem.202004380. Epub 2021 Jan 19.
We report investigations of the use of cucurbit[8]uril (CB[8]) macrocycles as an antidote to counteract the in vivo biological effects of phencyclidine. We investigate the binding of CB[8] and its derivative Me CB[8] toward ten drugs of abuse (3-9, 12-14) by a combination of H NMR spectroscopy and isothermal titration calorimetry in phosphate buffered water. We find that the cavity of CB[8] and Me CB[8] are able to encapsulate the 1-amino-1-aryl-cyclohexane ring system of phencyclidine (PCP) and ketamine as well as the morphinan skeleton of morphine and hydromorphone with K values ≤50 nm. In vitro cytotoxicity (MTS metabolic and adenylate kinase cell death assays in HEK293 and HEPG2 cells) and in vivo maximum tolerated dose studies (Swiss Webster mice) which were performed for Me CB[8] indicated good tolerability. The tightest host⋅guest pair (Me CB[8]⋅PCP; K =2 nm) was advanced to in vivo efficacy studies. The results of open field tests demonstrate that pretreatment of mice with Me CB[8] prevents subsequent hyperlocomotion induction by PCP and also that treatment of animals previously dosed with PCP with Me CB[8] significantly reduces the locomotion levels.
我们报告了使用葫芦[8]脲（CB[8]）大环作为解毒剂来抵消苯环利定体内生物效应的研究。我们通过 H NMR 光谱和等温热滴定法在磷酸盐缓冲水中研究了 CB[8]及其衍生物 Me CB[8]与十种滥用药物（3-9、12-14）的结合情况。我们发现 CB[8]和 Me CB[8]的腔能够包裹苯环利定（PCP）和氯胺酮的 1-氨基-1-芳基环己烷环系统，以及吗啡和氢吗啡酮的吗啡烷骨架，K 值≤50nm。体外细胞毒性（HEK293 和 HEPG2 细胞中的 MTS 代谢和腺苷酸激酶细胞死亡测定）和体内最大耐受剂量研究（瑞士 Webster 小鼠）表明 Me CB[8]具有良好的耐受性。最紧密的主体-客体对（Me CB[8]⋅PCP；K=2nm）被推进到体内功效研究。旷场试验的结果表明，用 Me CB[8]预处理小鼠可防止随后由 PCP 引起的过度活动诱导，并且用 Me CB[8]治疗先前用 PCP 给药的动物可显著降低运动水平。
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