Protection of pancreatic islets from oxidative cell death by a peripherally-active morphinan with increased drug safety.

Autor:	Scholz O; Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany; Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Neuherberg, D-85764 Neuherberg, Germany., Huß E; Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany; Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Neuherberg, D-85764 Neuherberg, Germany., Otter S; Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany; Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Neuherberg, D-85764 Neuherberg, Germany., Herebian D; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital, Heinrich Heine University, D-40225 Düsseldorf, Germany., Hamacher A; Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany; Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany., Levy LM; Taros Chemicals GmbH & Co. KG, D-44227 Dortmund, Germany., Hristeva S; Taros Chemicals GmbH & Co. KG, D-44227 Dortmund, Germany., Sanz M; Taros Chemicals GmbH & Co. KG, D-44227 Dortmund, Germany., Ajani H; Taros Chemicals GmbH & Co. KG, D-44227 Dortmund, Germany., Puentes AR; Taros Chemicals GmbH & Co. KG, D-44227 Dortmund, Germany., Hoffmann T; Taros Chemicals GmbH & Co. KG, D-44227 Dortmund, Germany., Hogeback J; A&M Labor für Analytik und Metabolismusforschung Service GmbH, D-50126 Bergheim, Germany., Unger A; Lead Discovery Center GmbH & Co. KG, D-44227 Dortmund, Germany., Terheyden S; Lead Discovery Center GmbH & Co. KG, D-44227 Dortmund, Germany., Reina do Fundo M; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Neuherberg, D-85764 Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany., Dewidar B; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Neuherberg, D-85764 Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany., Roden M; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Neuherberg, D-85764 Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University, D-40225 Düsseldorf, Germany., Lammert E; Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany; Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Neuherberg, D-85764 Neuherberg, Germany. Electronic address: lammert@hhu.de.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2023 Sep; Vol. 75, pp. 101775. Date of Electronic Publication: 2023 Jul 12.
DOI:	10.1016/j.molmet.2023.101775
Abstrakt:	Objective: Dextromethorphan (DXM) is a commonly used antitussive medication with positive effects in people with type 2 diabetes mellitus, since it increases glucose tolerance and protects pancreatic islets from cell death. However, its use as an antidiabetic medication is limited due to its central nervous side effects and potential use as a recreational drug. Therefore, we recently modified DXM chemically to reduce its blood-brain barrier (BBB) penetration and central side effects. However, our best compound interacted with the cardiac potassium channel hERG (human ether-à-go-go-related gene product) and the μ-opioid receptor (MOR). Thus, the goal of this study was to reduce the interaction of our compound with these targets, while maintaining its beneficial properties. Methods: Receptor and channel binding assays were conducted to evaluate the drug safety of our DXM derivative. Pancreatic islets were used to investigate the effect of the compound on insulin secretion and islet cell survival. Via liquor collection from the brain and a behavioral assay, we analyzed the BBB permeability. By performing intraperitoneal and oral glucose tolerance tests as well as pharmacokinetic analyses, the antidiabetic potential and elimination half-life were investigated, respectively. To analyze the islet cell-protective effect, we used fluorescence microscopy as well as flow cytometric analyses. Results: Here, we report the design and synthesis of an optimized, orally available BBB-impermeable DXM derivative with lesser binding to hERG and MOR than previous ones. We also show that the new compound substantially enhances glucose-stimulated insulin secretion (GSIS) from mouse and human islets and glucose tolerance in mice as well as protects pancreatic islets from cell death induced by reactive oxygen species and that it amplifies the effects of tirzepatide on GSIS and islet cell viability. Conclusions: We succeeded to design and synthesize a novel morphinan derivative that is BBB-impermeable, glucose-lowering and islet cell-protective and has good drug safety despite its morphinan and imidazole structures. Competing Interests: Declaration of competing interest E.L. declares the following competing financial interest: E.L. is inventor of the US patent 10,464,904 entitled “Dextrorphan-derivatives with suppressed central nervous activity” and the US patent 9,370,511 entitled “Morphinan-derivatives for treating diabetes and related disorders”. O.S., S.O., D.H., T.H., L.M.L., M.S. and E.L. further declare that another patent application has been submitted, entitled “Synthesis of dextrorotatory, antidiabetic morphinans with reduced hERG activity and MOP binding”. (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu