Synthesis and opioid activity of [D-Pro10]dynorphin A-(1-11) analogues with N-terminal alkyl substitution.
Synthesis and opioid activity of [D-Pro10]dynorphin A-(1-11) analogues with N-terminal alkyl substitution.
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N 末端烷基取代的 [D-Pro10] 强啡肽 A-(1-11) 类似物的合成和阿片类药物活性。
DOI：
10.1021/jm960747t
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Aldrich,JV
中科院分区：
文献类型：
--
作者：
Choi,H;Murray,TF;DeLander,GE;Schmidt,WK;Aldrich,JV
Several N-terminal di- and monoalkylated derivatives of [d-Pro10]dynorphin A-(1−11) were synthesized in order to explore the structure−activity relationships for antagonist vs agonist activity at κ-opioid receptors.N,N-Dialkylated andN-monoalkylated (alkyl = allyl, benzyl, and cyclopropylmethyl (CPM)) tyrosine derivatives were prepared from tyrosinetert-butyl ester and the corresponding alkyl halides. [d-Pro10]Dyn A-(2−11) was prepared by solid phase synthesis using Fmoc-protected amino acids, and the tyrosine derivatives were coupled to the peptide with BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate). Both the degree of substitution and the identity of the alkyl group affected κ-receptor affinity, selectivity, and efficacy. All of theN-monoalkylated derivatives exhibited much higher affinity (Ki< 0.05 nM) for κ receptors in the guinea pig cerebellum and greatly enhanced κ-receptor selectivity (Kiratio (κ/μ) > 200) compared to theN,N-dialkyl [d-Pro10]Dyn A-(1−11) analogues, although one disubstituted analogue,N,N-diCPM[d-Pro10]Dyn A-(1−11), retained high affinity (Ki= 0.19 nM) for κ receptors. Thus the introduction of the second alkyl group at the N-terminus lowered κ-receptor affinity and selectivity. TheN-allyl andN-CPM analogues were moderately potent agonists in the guinea pig ileum (GPI) assay, while theN-benzyl derivative was a weak agonist in this assay.In vivoin the phenylquinone abdominal stretching assay theN-CPM analogue exhibited potent antinociceptive activity (ED50= 1.1 μg/mouse), whileN-allyl[d-Pro10]Dyn A-(1−11) exhibited weak antinociceptive activity (ED50= 27 μg/mouse). For theN,N-dialkyl derivatives the identity of the N-terminal alkyl group affected the efficacy observed in the smooth muscle assays. TheN,N-diCPM analogue exhibited negligible agonist activity, andN,N-diallyl[d-Pro10]Dyn A-(1−11) showed weak antagonist activity against Dyn A-(1−13)NH2in the GPI. In contrast, theN,N-dibenzyl compound showed appreciable opioid agonist activity in this assay.In vivotheN,N-diallyl analogue exhibited weak antinociceptive activity (ED50= 26 μg/mouse in the phenylquinone abdominal stretching assay). TheN-monoalkylated peptides are among the most κ-selective opioid peptides reported to date, showing comparable or greater selectivity and higher affinity than the κ-selective non-peptide agonists U-50,488 and U-69,593. TheN,N-diCPM andN,N-diallyl peptides are lead compounds in the development of peptide-based κ-receptor antagonists.
