Identification of stabilized dynorphin derivatives for suppressing tolerance in morphine-dependent rats.
Identification of stabilized dynorphin derivatives for suppressing tolerance in morphine-dependent rats.
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鉴定用于抑制吗啡依赖性大鼠耐受性的稳定强啡肽衍生物。
DOI：
10.1023/b:pham.0000036920.50291.5b
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发表时间：
2004
影响因子：
3.7
通讯作者：
Hochhaus,Günther
中科院分区：
文献类型：
--
作者：
Al-Fayoumi,SulimanI;Brugos,Boglarka;Arya,Vikram;Mulder,Esther;Eppler,Barbel;Mauderli,AndreP;Hochhaus,Günther
目的：强啡肽A（1-13）[DynA（1 - 13）]和类似肽对吗啡诱导的效应，如耐受和戒断，有调节作用。由于人代谢酶的广泛代谢导致人血浆中的半衰期小于1 min，因此这些药物目前的治疗潜力有限。本研究的目的是确定稳定的强啡肽A（强啡肽A）衍生物，以确定其在人体血浆中的代谢途径，并评估是否保留的药效学活性。方法。肽在人体血浆中的稳定性进行了测试usingin vitrometabolism studies有和没有酶抑制剂。在高效液相色谱（HPLC）分离后，通过质谱法对生成的代谢产物进行鉴别。结果：虽然强啡肽A（1-13）的酰胺化能够阻止大部分C-末端的降解，但强啡肽A（1-10）酰胺的代谢仍能被巯甲丙脯酸敏感酶继续，提示强啡肽A（1-13）酰胺是一种更好的补充稳定剂。在N-末端进一步稳定的两种Dyn A（1-13）酰胺衍生物，[D-Tyr 1]-Dyn A（1-13）酰胺和[N-Met-Tyr 1]-Dyn A（1-13）酰胺，在血浆中的半衰期分别为70和130 min。最稳定的衍生物[N-Met-Tyr 1]-Dyn A（1-13）酰胺被成功地测试为保留药理活性以调节抗伤害感受活性。[N-Met-Tyr 1]-Dyn A（1-13）酰胺在甩尾试验中显示出显著的稳定性和抗伤害感受活性，从而指出该衍生物在疼痛管理中的临床潜力以及其在抑制阿片耐受和戒断中的潜在活性。
Purpose.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.Methods.The stability of peptides in human plasma was tested usingin vitrometabolism studies with and without enzyme inhibitors. Identification of the generated metabolites was performed by mass spectrometry after high performance liquid chromatography (HPLC) separation. Thein vivoactivity of a stabilized dynorphin was tested by tail-flick assay in morphine-tolerant rats.Results.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) amide and [N-Met-Tyr1]-Dyn A(1-13) amide, showed half-lives in plasma of 70 and 130 min, respectively. The most stable derivative [N-Met-Tyr1]-Dyn A(1-13) amide was tested successfully for retention of the pharmacological activity in modulating antinociceptive activity.Conclusions.[N-Met-Tyr1]-Dyn A(1-13) amide showed significant stability and antinociceptive activity in the tail-flick test, thus pointing to the clinical potential of this derivative in the management of pain as well as its potential activity in suppressing opiate tolerance and withdrawal.