Molecular recognition properties of water-soluble Prism[5]arene towards drugs of abuse.

Abstract

We report our study of the binding of a water soluble prism[5]arene (<b>WPr[5]</b>) 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 <b>WPr[5]</b>. Analysis of the complexation induced changes in chemical shift, backed up by molecular modelling, showed that <b>WPr[5]</b> 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 <b>WPr[5]</b>. 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 <b>WPr[5]</b>•fentanyl and -9.26 ± 0.04 kcal mol^-1 for <b>WPr[5]</b>•MDMA. We performed <i>in vitro</i> 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 <b>WPr[5]</b> is well tolerated up to 45 mg/kg.

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