Preclinical studies to treat diabetes mellitus using novel DXM derivatives

Issue The over-the-counter drug dextromethorphan (DXM) shows anti-diabetic and islet cell-protective effects in vitro and in vivo, without inducing hypoglycemia. However, DXM is able to pass the blood-brain barrier (BBB) and potential CNS-related side effects limit its use as anti-diabetic drug. We chemically generated novel derivatives of DXM to prevent compound distribution to the CNS, while maintaining the anti-diabetic and islet cell-protective potential.

Methods Isolated mouse or human pancreatic islets were used to investigate the effect of the derivatives on glucose-stimulated insulin secretion. Via liquor collection from the brain and by tandem mass spectrometry we analyzed the BBB passage of the derivatives. By performing behavioral tests and glucose tolerance tests, the neurological impairment and anti-diabetic potential was measured, respectively. To analyze the islet cell-protective effect of the derivatives we used laser scanning microscopy. Significance was determined by unpaired two-sided Student’s t-test and one-way or two-way ANOVA with Tukey’s multiple comparison test.

Results Specific derivatives showed a reduced BBB permeability and did not lead to neurological impairment in mice. Furthermore, treatment resulted in increased glucose-stimulated insulin secretion in vitro and improved glucose tolerance in vivo. Notably, our lead compound protected human pancreatic islets against the beta cell toxin streptozotocin stronger than an existing anti-diabetic drug.

Conclusion We designed novel DXM derivatives with a reduced BBB passage and without CNS-related side effects, while the insulinotropic, blood glucose-lowering, and islet cell-protective effects were maintained or even improved. Therefore, our derivatives have the potential to be developed into a new class of anti-diabetic drugs.

Interessenskonflikt

E.L., T.M., E.M., D.H. hold a US patent (WO 2013 / 029762 A1) and EU patent (EP: 2747754 B1) entitled „morphinan-derivates for treating diabetes and related disorders“; E.L., T.M., E.M., D.H., S.O., A.W. hold a US patent (WO 2017 / 093519) and EU patent application on dextrorphan-derivates with suppressed central nervous activity (PCT / EP2016/079645).

Publikationsverlauf

Artikel online veröffentlicht:
06. Mai 2021