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In Vitro and In Vivo Sequestration of Phencyclidine by Me 4 Cucurbit[8]uril **
Author(s) -
Murkli Steven,
Klemm Jared,
Brockett Adam T.,
Shuster Michael,
Briken Volker,
Roesch Matthew R.,
Isaacs Lyle
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202004380
Subject(s) - in vivo , phencyclidine , chemistry , pharmacology , isothermal titration calorimetry , ketamine , stereochemistry , biochemistry , receptor , medicine , biology , nmda receptor , microbiology and biotechnology , anesthesia
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 4 CB[8] toward ten drugs of abuse ( 3 – 9 , 12 – 14 ) by a combination of 1 H NMR spectroscopy and isothermal titration calorimetry in phosphate buffered water. We find that the cavity of CB[8] and Me 4 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 d values ≤50 n m . 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 4 CB[8] indicated good tolerability. The tightest host⋅guest pair (Me 4 CB[8]⋅PCP; K d =2 n m ) was advanced to in vivo efficacy studies. The results of open field tests demonstrate that pretreatment of mice with Me 4 CB[8] prevents subsequent hyperlocomotion induction by PCP and also that treatment of animals previously dosed with PCP with Me 4 CB[8] significantly reduces the locomotion levels.