ArticleMolecular metabolism2023
Protection of pancreatic islets from oxidative cell death by a peripherally-active morphinan with increased drug safety.
Article in Molecular metabolism, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
2 citing papers in PubMed, 2 citations in OpenAlex.
- CHAC1-linked NRF2 protein expression participates in pancreatic islet protection by dextrorphan.iScience · 2026Article
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Authors and funding
18 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveDextromethorphan (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.
methodsReceptor 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.
resultsHere, 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.
conclusionsWe 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.
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