Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 27, Issue 9, Pages 3098-3105Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202004380
Keywords
cucurbituril; hyperlocomotion; molecular recognition; phencyclidine; sequestration agents
Categories
Funding
- National Institutes of Health [T32 GM080201, CA168365, GM132345]
- National Science Foundation [CHE-1404911]
- Department of Education GAANN fellowships [P200A150033]
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The study found that CB[8] and Me4CB[8] can encapsulate the molecular structures of various drugs of abuse, and Me4CB[8] has good tolerability. Experimental results showed that pretreating with Me4CB[8] can prevent and reduce excessive locomotion induced by PCP.
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 Me4CB[8] toward ten drugs of abuse (3-9, 12-14) by a combination of H-1 NMR spectroscopy and isothermal titration calorimetry in phosphate buffered water. We find that the cavity of CB[8] and Me4CB[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-d 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 Me4CB[8] indicated good tolerability. The tightest host.guest pair (Me4CB[8].PCP; K-d=2 nm) was advanced to in vivo efficacy studies. The results of open field tests demonstrate that pretreatment of mice with Me4CB[8] prevents subsequent hyperlocomotion induction by PCP and also that treatment of animals previously dosed with PCP with Me4CB[8] significantly reduces the locomotion levels.
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