Protection of pancreatic islets from oxidative cell death by a peripherally-active morphinan with increased drug safety
Okka Scholz, Elena Huß, Silke Otter, Diran Herebian, Anna Hamacher, Laura Mariana Levy, Stanimira Hristeva, Miguel Sanz, Haresh Ajani, Alfredo Rodriguez Puentes, Torsten Hoffmann, Jens Hogeback, Anke Unger, Susanne Terheyden, Michelle Reina do Fundo, Bedair Dewidar, Michael Roden, Eckhard Lammert
Molecular Metabolism, July 2023, https://doi.org/10.1016/j.molmet.2023.101775
Abstract:
Dextromethorphan (DXM) is a commonly used antitussive medication with positive effects in people with type 2 diabetes mellitus, since it increases glucose tolerance and protects pancreatic islets from cell death. However, its use as an antidiabetic medication is limited due to its central nervous side effects and potential use as a recreational drug. Therefore, we recently modified DXM chemically to reduce its blood–brain barrier (BBB) penetration and central side effects. However, our best compound interacted with the cardiac potassium channel hERG (human ether-à-go-go-related gene product) and the μ-opioid receptor (MOR). Thus, the goal of this study was to reduce the interaction of our compound with these targets, while maintaining its beneficial properties.
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