Peripherally Restricted DXO Derivates for the Treatment of Diabetes Mellitus

Introduction:

We have recently shown that the N-Methyl-D-Aspartate receptor (NMDAR) antagonist and over-the-counter drug dextromethorphan (DXM) and its active metabolite dextrorphan (DXO) have antidiabetic and islet cell protective properties. However, both molecules are associated with central nervous system related side effects. To reduce these effects, we are currently developing and testing derivates of DXO that have a reduced blood-brain barrier (BBB) permeability while having a preserved antidiabetic potential.

Methods:

For in vitro experiments, we use isolated mouse and human pancreatic islets to assess the ability of the derivates to increase glucose-stimulated insulin secretion. To analyze the islet cell protective effect of the derivates we apply laser scanning microscopy. For in vivo experiments, we perform glucose tolerance tests and rotarod and hanging wire tests, to test the antidiabetic potential and neurological impairment, respectively. Via liquor collection and tandem mass spectrometry we analyze the BBB permeability of the derivates.

Results:

Several tested derivates of DXO have a reduced BBB permeability, do not lead to significant behavioral effects in mice, increase glucose-stimulated insulin secretion and improve glucose tolerance. Furthermore, our lead compound has islet cell protective effects.

Conclusion:

Our preclinical studies reveal that we are able to develop novel derivates of DXO that have a reduced BBB permeability without losing the antidiabetic properties of the starting molecule. Therefore, our compounds may have the potential to be developed as a new class of drugs for diabetes treatment.