Electronic Supporting Data for Molecular Recognition Properties of Water Soluble Prism[5]arene Toward Drugs of Abuse

We report our study of the binding of a water soluble prism[5]arene (WPr[5]) toward a panel of 11 drugs of abuse by a combination of 1H NMR spectroscopy, isothermal titration calorimetry (ITC), and molecular modelling. 1H NMR spectroscopy showed that the narrower drugs (fentanyl, methamphetamine, MDMA, mephedrone) exhibited dramatic upfield shifts ( up to -4.8 ppm) upon complexation due to the 5 convergent magnetically shielding naphthalene walls of WPr[5]. Analysis of the complexation induced changes in chemical shift, backed up by molecular modelling, showed that WPr[5] encircles the ammonium ion region to engage in cation- interactions rather than complexing the terminal aryl rings of the drug. The larger drugs (morphine, heroin, oxycodone, hydrocodone) do not undergo cavity inclusion binding with WPr[5]. Direct and competitive ITC was used to determine the binding constants and enthalpies of complexation in PBS which range up to 1.11 × 107 M-1 for WPr[5]•fentanyl and -9.26 ± 0.04 kcal mol-1 for WPr[5]•MDMA. We performed in vitro assays using HEK293 and Hep G2 cells which establish good cytocompatibility up to 33 M. Finally, an in vivo maximum tolerated dose study using female Swiss Webster mice showed that WPr[5] is well tolerated up to 45 mg/kg.