Fentanyl, a synthetic opioid analgesic, forms complexes with CDs with modest equilibrium binding affinities (Ka ~ 100–200 M-1). In this work, Sualphadex, Subetadex and Sugammadex with thioalkylcarboxyl groups of various chain length were prepared with their thioalkylhydroxyl analogues to assess their binding affinity towards fentanyl hydrochloride. The optimal CD (4-mercaptobutanoyl bCD) studied displays a remarkable affinity for the opioid of Ka = 66,500 M−1, the largest value reported for such an inclusion complex to date. One dimensional 1H Nuclear Magnetic Resonance (NMR) as well as Rotational Frame Overhauser Spectroscopy (2D-ROESY) experiments supported by molecular dynamics (MD) simulations suggest an unexpected binding behavior, with fentanyl able to bind the CD interior in one of two distinct orientations. Binding energies derived from the MD simulations correlate strongly with NMR-derived affinities highlighting its utility as a predictive tool for CD candidate optimization. The performance of these host molecules portends their utility as platforms for medical countermeasures for opioid exposure, as biosensors, and in other forensic science applications.
Mayer, B.P., Kennedy, D.J., Lau, E.Y. et al. Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl. Sci Rep 13, 2680 (2023). https://doi.org/10.1038/s41598-023-29662-1