Investigation of peripherally active and blood glucose-lowering dextromethorphan derivatives without central nervous side effects

Pancreatic islets represent the endocrine compartment of the pancreas and contain different hormone-releasing cell types, including insulin-secreting beta cells. These hormones are essential to maintain blood glucose concentrations within a narrow range (glucose homeostasis). The progressive dysfunction and demise of beta cells is associated with the onset and development of type 2 diabetes mellitus (T2DM), a not curable metabolic disorder that is accompanied by serious long-term complications. Several options for the treatment of diabetes are available, however, none of the currently available anti-diabetic drugs are able to stop disease progression. Thus, the development of beta cell protective agents that prevent or even reverse the onset of the disease is essential. The over-the-counter (OTC) drug dextromethorphan (DXM) shows anti-diabetic and islet cell protective effects in vitro and in vivo, without inducing life-threatening hypoglycemia. Furthermore, DXM reveals positive effects on diabetic long-term complications, including cardiovascular endpoints. However, DXM is able to pass the blood-brain barrier (BBB), and potential central nervous side effects limit its use as an anti-diabetic medication. Within this project, we generated a series of novel derivatives of DXM to prevent compound distribution to the central nervous system while maintaining or improving the beneficial properties of the molecule on peripheral tissues. We found that DXM derivatives with basic nitrogen-containing substituents showed a reduced BBB permeability and did not lead to neurological impairment in mice. Additionally, treatment with these derivatives resulted in increased glucose-stimulated insulin secretion from mouse and human pancreatic islets in vitro as well as elevated plasma insulin concentrations and improved glucose tolerance in vivo. Notably, the imidazole-containing DXM derivative Lam39 protected human islets against the beta cell toxin streptozotocin, whereas the existing anti-diabetic drug exendin-4 did not show a protective effect. Moreover, Lam39 was able to improve glucose tolerance in a mouse model of T2DM. In summary, we were able to design and synthesize novel structural derivatives of the OTC drug DXM with a reduced BBB passage and without central nervous side effects while the insulinotropic, blood glucose-lowering and islet cell protective effects of the original drug were maintained or even improved. Therefore, our novel DXM derivatives have the potential to be developed into a new class of anti-diabetic drugs.