PMID: 15359581Sep 14, 2004Paper

Identification of stabilized dynorphin derivatives for suppressing tolerance in morphine-dependent rats

Pharmaceutical Research
Suliman I Al-FayoumiGünther Hochhaus

Abstract

Modulatory actions on morphine-induced effects, such as tolerance and withdrawal, have been noted for dynorphin A(1-13) [Dyn A(1-13)] and similar peptides. These are currently of limited therapeutic potential due to extensive metabolism by human metabolic enzymes resulting in a half-life of less than 1 min in human plasma. The purpose of this study was to identify stabilized dynorphin A (Dyn A) derivatives, to determine their metabolic routes in human plasma, and to assess whether the pharmacodynamic activity is retained. The stability of peptides in human plasma was tested using in vitro metabolism studies with and without enzyme inhibitors. Identification of the generated metabolites was performed by mass spectrometry after high performance liquid chromatography (HPLC) separation. The in vivo activity of a stabilized dynorphin was tested by tail-flick assay in morphine-tolerant rats. Though amidation of the Dyn A(1-13) was able to stop the majority of C-terminal degradation, metabolism of Dyn A(1-10) amide continued by captopril sensitive enzymes, suggesting that Dyn A(1-13) amide is a better candidate for additional stabilization. Two Dyn A(1-13) amide derivatives further stabilized at the N-terminal end, [D-Tyr1]-Dyn A(1-13...Continue Reading

Citations

Apr 4, 2013·Journal of Medicinal Chemistry·Adriano MollicaVictor J Hruby
May 12, 2009·The AAPS Journal·Jane V Aldrich, Jay P McLaughlin
Jul 26, 2005·Peptides·Richard J Bodnar, Gad E Klein
Jun 12, 2020·Neuropharmacology·Kinga HartmanJerzy Silberring
Aug 1, 2008·Journal of Medicinal Chemistry·Morteza MalakoutikhahErnest Giralt

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