Peripherally active dextromethorphan derivatives lower blood glucose levels by targeting pancreatic islets. Issue 10 (21st October 2021)

• Record Type: Journal Article
• Authors: Scholz, Okka; Otter, Silke; Welters, Alena; Wörmeyer, Laura; Dolenšek, Jurij; Klemen, Maša Skelin; Pohorec, Viljem; Eberhard, Daniel; Mrugala, Jessica; Hamacher, Anna; Koch, Angela; Sanz, Miguel; Hoffmann, Torsten; Hogeback, Jens; Herebian, Diran; Klöcker, Nikolaj; Piechot, Alexander; Mayatepek, Ertan; Meissner, Thomas; Stožer, Andraž; Lammert, Eckhard
• Is Part Of: Cell chemical biology. Volume 28:Issue 10(2021)
• Page Start: 1474
• Page End: 1488.e7
• Publication Date: 2021-10-21
• Subjects: diabetes mellitus -- pancreatic islet -- insulin secretion -- drug discovery -- dextromethorphan -- electrophysiology -- blood-brain barrier -- blood glucose -- cell survival -- islet cell protection; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2021.05.011
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical abstract: Highlights: DXM was chemically modified to prevent its effects on the CNS The DXM derivatives protect mouse and human pancreatic islets from cell death The derivatives lower blood glucose levels without affecting the behavior of mice DXM derivatives represent anti-diabetic, cell-protective pharmacologic agents Abstract : Dextromethorphan is used as antitussive medication, but has central nervous side effects that prevent its use for treatment of diverse illnesses. Here, Scholz et al. designed and synthesized derivatives of dextromethorphan without such side effects. The derivates are characterized by strong anti-diabetic and pancreatic islet cell-protective properties.