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Anthracene-Walled Acyclic CB[n] Receptors: in?vitro and in?vivo Binding Properties toward Drugs of Abuse |
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| Authors: | Delaney DiMaggio Dr Adam T Brockett Michael Shuster Dr Steven Murkli Dr Canjia Zhai David King Brona O'Dowd Dr Ming Cheng Dr Kimberly Brady Prof?Dr Volker Briken Prof?Dr Matthew R Roesch Prof?Dr Lyle Isaacs |
| Affiliation: | 1. Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742 USA;2. Department of Psychology and Program in Neuroscience and Cognitive Science (NACS), University of Maryland, College Park, MD 20742 USA;3. Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742 USA |
| Abstract: | We report studies of the interaction of six acyclic CBn]-type receptors toward a panel of drugs of abuse by a combination of isothermal titration calorimetry and 1H NMR spectroscopy. Anthracene walled acyclic CBn] host ( M3 ) displays highest binding affinity toward methamphetamine (Kd=15 nM) and fentanyl (Kd=4 nM). Host M3 is well tolerated by Hep G2 and HEK 293 cells up to 100 μM according to MTS metabolic and adenylate kinase release assays. An in vivo maximum tolerated dose study with Swiss Webster mice showed no adverse effects at the highest dose studied (44.7 mg kg?1). Host M3 is not mutagenic based on the Ames fluctuation test and does not inhibit the hERG ion channel. In vivo efficacy studies showed that pretreatment of mice with M3 significantly reduces the hyperlocomotion after treatment with methamphetamine, but M3 does not function similarly when administered 30 seconds after methamphetamine. |
| Keywords: | Cucurbituril methamphetamine hyperlocomotion sequestration agent molecular recognition |