Synthesis and opioid activity of side-chain-to-side-chain cyclic dynorphin A-(1-11) amide analogues cyclized between positions 2 and 5. 1. Substitutions in position 3.
Synthesis and opioid activity of side-chain-to-side-chain cyclic dynorphin A-(1-11) amide analogues cyclized between positions 2 and 5. 1. Substitutions in position 3.
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在位置 2 和位置 5 之间环化的侧链至侧链环状强啡肽 A-(1-11) 酰胺类似物的合成和阿片样活性。 1. 位置 3 的取代。
DOI：
10.1021/jm030298e
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Aldrich,JaneV
中科院分区：
文献类型：
--
作者：
Vig,BalvinderS;Murray,ThomasF;Aldrich,JaneV
cyclo[d-Asp2,Dap5]Dyn A-(1−13)NH2(Dap, 2,3-diaminopropionic acid; Dyn A, dynorphin A), synthesized previously in our laboratory, showed sub-nanomolar affinity for κ opioid receptors and potent agonist activity in the guinea pig ileum assay (Arttamangkul et al., J. Med. Chem.1995,38, 2410−2417). Various modifications were made in position 3 ofcyclo[d-Asp2,Dap5]Dyn A-(1−11)NH2that could influence the opioid receptor affinity, selectivity, and/or efficacy of this peptide. An optimized orthogonal synthetic strategy was developed for the synthesis of these cyclic peptides in which the final peptides could be cleaved from the solid support with trifluoroacetic acid. Substitutions of Gly3by Ala,d-Ala, Trp, andd-Trp incyclo[d-Asp2,Dap5]Dyn A-(1−11)NH2and its linear counterpart [d-Asp2,Dap5]Dyn A-(1−11)NH2were generally well tolerated by both κ and μ opioid receptors. Despite differences in the size and stereochemistry of the substitutions, most of the peptides (except forcyclo[d-Asp2,Pro3,Dap5]Dyn A-(1−11)NH2and [d-Asp2,d-Ala3, Dap5]Dyn A-(1−11)NH2) exhibited low nanomolar affinity for both κ (Ki= 0.21 to 2.2 nM) and μ (Ki= 0.22 to 7.27 nM) opioid receptors. All of the 3-substituted cyclic and linear analogues synthesized showed reduced affinity for δ opioid receptors. Incorporation ofd-Ala at position 3 ofcyclo[d-Asp2,Dap5]Dyn A-(1−11)NH2exhibited 2-fold higher κ opioid receptor affinity and 16-fold higher selectivity for κ over μ opioid receptors than the parent cyclic peptide. In contrast, substitution of Ala at position 3 resulted in an analogue with 2.4-fold lower affinity and very low preference for κ over μ opioid receptors. The Trp andd-Trp cyclic and linear analogues exhibited similar nanomolar affinities for κ opioid receptors.cyclo[d-Asp2,Pro3,Dap5]Dyn A-(1−11)NH2showed the largest decreases in affinity for all three opioid receptors compared to the parent cyclic peptide. Except forcyclo[d-Asp2, Pro3,Dap5]Dyn A-(1−11)NH2, which was a partial agonist, all of the cyclic peptides exhibited full agonist activity in the adenylyl cyclase assay using cloned κ opioid receptors.
