Abstract
AbstractCyclodextrins (CDs) have been previously shown to display modest equilibrium binding affinities (Ka ~ 100–200 M-1) for the synthetic opioid analgesic fentanyl. In this work, we describe the synthesis of new CDs possessing extended thioalkylcarboxyl or thioalkylhydroxyl moieties and assess their binding affinity towards fentanyl hydrochloride. The optimal CD 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 work 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.
Funder
Lawrence Livermore National Laboratory
U. S. Department of Energy
Publisher
Springer Science and Business Media LLC
Reference74 articles.
1. Clotz, M. A. & Nahata, M. C. Clinical uses of fentanyl, sufentanil, and alfentanil. Clin. Pharm. 10, 581–593 (1991).
2. Miró, Ò., Gil, V. & Peacock, W. F. Morphine in acute heart failure: Good in relieving symptoms, bad in improving outcomes. J. Thorac. Dis. 9, 1831–1834 (2017).
3. Chen, A. & Ashburn, M. A. Cardiac effects of opioid therapy. Pain Med. 16, S27–S31 (2015).
4. Lipinski, P. F. J. et al. Fentanyl family at the mu-opioid receptor: Uniform assessment of binding and computational analysis. Molecules 24, 740 (2019).
5. Lipinski, P. F. J., Jaronczyk, M., Dobrowolski, J. C. & Sadlej, J. Molecular dynamics of fentanyl bound to μ-opioid receptor. J. Mol. Model 25, 144 (2019).
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献