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Title: In Vitro and In Vivo Sequestration of Phencyclidine by Me 4 Cucurbit[8]uril**
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 Me4CB[8] toward ten drugs of abuse (39,1214) by a combination of1H 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 withKdvalues ≤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;Kd=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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NSF-PAR ID:
10255760
Author(s) / Creator(s):
 ;  ;  ;  ;  ;  ;  
Publisher / Repository:
Wiley Blackwell (John Wiley & Sons)
Date Published:
Journal Name:
Chemistry – A European Journal
Volume:
27
Issue:
9
ISSN:
0947-6539
Page Range / eLocation ID:
p. 3098-3105
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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