Peripherally active dextromethorphan derivatives lower blood glucose levels by targeting pancreatic islets

Cell Chem Biol. 2021 Oct 21;28(10):1474-1488.e7. doi: 10.1016/j.chembiol.2021.05.011. Epub 2021 Jun 11.

Abstract

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.

Keywords: blood glucose; blood-brain barrier; cell survival; dextromethorphan; diabetes mellitus; drug discovery; electrophysiology; insulin secretion; islet cell protection; pancreatic islet.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blood Glucose / analysis*
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Calcium / metabolism
  • Dextromethorphan / analogs & derivatives
  • Dextromethorphan / metabolism
  • Dextromethorphan / pharmacology*
  • Dextromethorphan / therapeutic use
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Type 2 / pathology
  • Drug Design
  • Glucagon-Like Peptide-1 Receptor / agonists
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Humans
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Insulin / blood
  • Insulin / metabolism
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Male
  • Membrane Potentials / drug effects
  • Mice, Inbred C57BL

Substances

  • Blood Glucose
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Insulin
  • Dextromethorphan
  • Calcium