Peripherally active dextromethorphan derivatives lower blood glucose levels by targeting pancreatic isletsBy Institute of Physiology on 16. 06. 2021
Authors: Okka Scholz, Silke Otter, Alena Welters, Laura Wörmeyer, Jurij Dolenšek, Maša Skelin Klemen, Viljem Pohorec, Daniel Eberhard, Jessica Mrugala, Anna Hamacher, Angela Koch, Miguel Sanz, Torsten Hoffman, Jens Hogeback, Diran Herebian, Nikolaj Klöcker, Alexander Piechot, Ertan Mayatepek, Thomas Meissner, Andraž Stožer, Eckhard Lammert
Journal: Cell Chemical Biology
Dextromethorphan (DXM) acts as cough suppressant via its central action. Cell-protective effects of this drug have been reported in peripheral tissues, making DXM potentially useful for treatment of several common human diseases, such as type 2 diabetes mellitus (T2DM). Pancreatic islets are among the peripheral tissues that positively respond to DXM, and anti-diabetic effects of DXM were observed in two placebo-controlled, randomized clinical trials in humans with T2DM. Since these effects were associated with central side effects, we here developed chemical derivatives of DXM that pass the blood-brain barrier to a significantly lower extent than the original drug. We show that basic nitrogen-containing residues block central adverse events of DXM without reducing its anti-diabetic effects, including the protection of human pancreatic islets from cell death. These results show how to chemically modify DXM, and possibly other morphinans, as to exclude central side effects, while targeting peripheral tissues, such as pancreatic islets.