Peripherally active dextromethorphan derivatives lower blood glucose levels by targeting pancreatic islets.
Cell Chem Biol
; 28(10): 1474-1488.e7, 2021 10 21.
Article
en En
| MEDLINE
| ID: mdl-34118188
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Glucemia
/
Islotes Pancreáticos
/
Dextrometorfano
/
Hipoglucemiantes
Tipo de estudio:
Clinical_trials
/
Prognostic_studies
Límite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
Cell Chem Biol
Año:
2021
Tipo del documento:
Article