Work

In Vitro and In Vivo Sequestration of Phencyclidine by Me 4 Cucurbit[8]uril**

Year: 2020

Type: article

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 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.

Source: Chemistry - A European Journal

DOI: 10.1002/chem.202004380