Structure-activity relationships of arodyn, a novel acetylated kappa opioid receptor antagonist
Structure-activity relationships of arodyn, a novel acetylated kappa opioid receptor antagonist
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DOI：
10.1111/j.1399-3011.2005.00216.x
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发表时间：
2005-03-01
期刊：
影响因子：
--
通讯作者：
Aldrich, JV
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文献类型：
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作者：
Bennett, MA;Murray, TF;Aldrich, JV
Bennett， M. A, Murray， T. F. & Aldrich， J. v . (2002) J. Med. Chem. (2002) J. Med. Chem.。（vol. 45, pp. 5617-5619）是kappa阿片受体选择性肽[K-i(kappa) = 10 nM， K-i比值(kappa/mu/delta) = 1/174/583]，对kappa阿片受体具有拮抗剂活性。本研究制备了一系列的苦苷类似物，并对其进行了评价，探讨了苦苷类似物的构效关系；这包括整个arodyn序列的丙氨酸扫描，n端“消息”序列的顺序同分异构体d -氨基酸替换，位置1-3的NMePhe单独替换，以及位置1的修饰。α取代衍生物的结果表明，Arg(6)和Arg(7)是阿片受体与阿片苷纳米摩尔结合亲和力的最重要残基。其他碱性残基(Arg(4), Arg（9)和Lys(11)）的Ala取代导致对kappa阿片受体的亲和力降低较低（与阿片苷相比降低了三到五倍）。特别有趣的是，虽然[Ala(10)]阿罗dyn表现出与阿罗dyn相似的kappa阿片受体结合，但它表现出更高的kappa与mu阿片受体选择性[K-i比(kappa/mu) = 1/350]，因为阿罗dyn对mu阿片受体的亲和力损失了两倍。令人惊讶的是，Tyr(1)类似物显示kappa阿片受体亲和力降低了7倍，这表明arodyn表现出明显不同于Dyn a的SAR；在使用稳定表达kappa阿片受体的中国仓鼠卵巢细胞进行的腺苷酸环化酶试验中，阿片丹也出人意料地表现出逆激动剂活性。NMePhe在1位上的取代得到了[NMePhe(1)]阿罗丁，其具有高亲和力[K-i(kappa) = 4.56 nM]和对kappa阿片样受体的特殊选择性[K-i比(kappa/mu/delta) = 1/1100/> 2170]。该肽在腺苷酸环化酶实验中显示出拮抗活性，逆转了10 nM Dyn A-(1-13)NH2的激动作用。因此[NMePhe(1)]阿罗丁是一种高度kappa阿片受体选择性拮抗剂，可能是研究kappa阿片受体介导活性的有用药理学工具。
We previously reported that the novel dynorphin A (Dyn A, Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln) analog arodyn (Ac[Phe(1,2,3), Arg(4), D-Ala(8)] Dyn A-(1-11)NH2, Bennett, M. A., Murray, T. F. & Aldrich, J.V. (2002) J. Med. Chem. vol. 45, pp. 5617-5619) is a kappa opioid receptor-selective peptide [K-i(kappa) = 10 nM, K-i ratio (kappa/mu/delta) = 1/174/583] which exhibits antagonist activity at kappa opioid receptors. In this study, a series of arodyn analogs was prepared and evaluated to explore the structure activity relationships (SAR) of this peptide; this included an alanine scan of the entire arodyn sequence, sequential isomeric D-amino acid substitution in the N-terminal 'message' sequence, NMePhe substitution individually in positions 1-3, and modifications in position 1. The results for the Ala-substituted derivatives indicated that Arg(6) and Arg(7) are the most important residues for arodyn's nanomolar binding affinity for kappa opioid receptors. Ala substitution of the other basic residues (Arg(4), Arg(9) and Lys(11)) resulted in lower decreases in affinity for kappa opioid receptors (three- to fivefold compared with arodyn). Of particular interest, while [Ala(10)] arodyn exhibits similar kappa opioid receptor binding as arodyn, it displays higher kappa vs. mu opioid receptor selectivity [K-i ratio (kappa/mu) = 1/350] than arodyn because of a twofold loss in affinity at mu opioid receptors. Surprisingly, the Tyr(1) analog exhibits a sevenfold decrease in kappa opioid receptor affinity, indicating that arodyn displays significantly different SAR than Dyn A; [Tyr(1)] arodyn also unexpectedly exhibits inverse agonist activity in the adenylyl cyclase assay using Chinese hamster ovary cells stably expressing kappa opioid receptors. Substitution of NMePhe in position 1 gave [NMePhe(1)] arodyn which exhibits high affinity [K-i(kappa) = 4.56 nM] and exceptional selectivity for kappa opioid receptors [ K-i ratio (kappa/mu/delta) = 1/1100/> 2170]. This peptide exhibits antagonistic activity in the adenylyl cyclase assay, reversing the agonism of 10 nM Dyn A-(1-13)NH2. Thus [NMePhe(1)] arodyn is a highly kappa opioid receptor-selective antagonist that could be a useful pharmacological tool to study kappa opioid receptor-mediated activities.