In Vitro and In Vivo Sequestration of Phencyclidine by Me4 Cucurbit[8]uril*.
Steven Murkli, Jared Klemm, Adam T. Brockett, Michael Shuster, Volker Briken, Matthew R Roesch, Lyle Isaacs
Chemistry - A European Journal February 10, 2021 DOI: 10.1002/chem.202004380 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Swiss Webster mice (in vivo studies); HEK293 and HEpG2 cells (in vitro assays) |
| Interventions | Cucurbit[8]uril (CB[8]) phencyclidine |
| Measures | 1H NMR spectroscopy, isothermal titration calorimetry, MTS metabolic assay, adenylate kinase cell death assay, open field test |
| Keywords | Cucurbituril Hyperlocomotion Molecular recognition Phencyclidine Sequestration agents |
| Key findings | CB[8] and Me4CB[8] bind PCP, ketamine, morphine, and hydromorphone with Kd values of 50 nM or less, with Me4CB[8] and PCP forming the tightest complex (Kd = 2 nM). In mice, pretreatment with Me4CB[8] prevented PCP-induced hyperlocomotion, and treatment after PCP dosing significantly reduced locomotion levels. |
Abstract
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 Me4 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 Me4 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 Kd 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 Me4 CB[8] indicated good tolerability. The tightest host⋅guest pair (Me4 CB[8]⋅PCP; Kd =2 nm) was advanced to in vivo efficacy studies. The results of open field tests demonstrate that pretreatment of mice with Me4 CB[8] prevents subsequent hyperlocomotion induction by PCP and also that treatment of animals previously dosed with PCP with Me4 CB[8] significantly reduces the locomotion levels.