Synthesis and opioid activity of 2-substituted dynorphin A-(1-13) amide analogues.
Synthesis and opioid activity of 2-substituted dynorphin A-(1-13) amide analogues.
复制标题
2-取代的强啡肽 A-(1-13) 酰胺类似物的合成和阿片类药物活性。
DOI：
10.1111/j.1399-3011.1992.tb01454.x
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发表时间：
1992
期刊：
影响因子：
--
通讯作者：
Aldrich,JV
中科院分区：
文献类型：
--
作者：
Story,SC;Murray,TF;Delander,GE;Aldrich,JV
A series of 2‐substituted dynorphin A‐(1‐13) amide (Dyn A‐(1‐13)NH2) analogues was prepared by solid phase peptide synthesis and evaluated for opioid receptor affinities in radioligand binding assays and for opioid activity in the guinea pig ileum (GPI) assay. Amino acid substitution at the 2 position produced marked differences in both opioid receptor affinities and potency in the GPI assay; Kivalues for the analogues in the radioligand binding assays and IC50values in the GPI assay varied over three to four orders of magnitude. The parent peptide, Dyn A‐(1‐13)NH2, exhibited the greatest affinity and selectivity for kappa receptors and was the most potent peptide examined in the GPI assay. The most important determinant of opioid receptor selectivity and opioid potency for the synthetic analogues was the stereochemistry of the amino acid at the 2 position. Except for [D‐Lys2]Dyn A‐(1‐13)NH2in the kappa receptor binding assay, the analogues containing a D‐amino acid at position 2 were much more potent in all of the assays than their corresponding isomers containing an L‐amino acid at this position. The L‐amino acid‐substituted analogues generally retained some selectivity for kappa opioid receptors. The more potent derivatives with a D‐amino acid in position 2, however, preferentially interacted with mu opioid receptors. Introduction of a positively charged amino acid into the 2 position generally decreased opioid receptor affinities and potency in the GPI assay.
