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

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.
Competing Interests: Declaration of interests S.O., A.W., D.H., T. M., E.M., and E. L. declare the following competing financial interests: these authors are inventors of the US patent 10,464,904 entitled “Dextrorphan-derivatives with suppressed central nervous activity”; and T.M. and E.L. are inventors of the US patent 9,370,511 entitled “Morphinan-derivatives for treating diabetes and related disorders.”
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