Molecular recognition properties of water-soluble Prism[5]arene towards 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 (Δ 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-π 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 μM. 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.