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新型混合 NOP/阿片受体肽激动剂。

Novel Mixed NOP/Opioid Receptor Peptide Agonists.

机构信息

Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, Ferrara 44121, Italy.

Department of Neuroscience and Rehabilitation, Section of Pharmacology, University of Ferrara, Via Fossato di Mortara 17/19, Ferrara 44121, Italy.

出版信息

J Med Chem. 2021 May 27;64(10):6656-6669. doi: 10.1021/acs.jmedchem.0c02062. Epub 2021 May 17.

DOI:10.1021/acs.jmedchem.0c02062
PMID:33998786
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8279409/
Abstract

The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt,Xaa]N/OFQ(1-13)-NH were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr and Thr at the N-terminal portion of N/OFQ(1-13)-NH with the noncanonical amino acid Dmt. [Dmt]N/OFQ(1-13)-NH has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an model of cough.

摘要

孤啡肽/孤啡肽 FQ（N/OFQ）/N/OFQ 受体（NOP）系统控制着不同的生物学功能，包括疼痛和咳嗽反射。混合 NOP/阿片受体激动剂产生与强阿片类药物相似的效果，但副作用较小。在这项工作中，合成了 31 种具有通式[Tyr/Dmt，Xaa]N/OFQ（1-13）-NH 的肽，并对其在人重组 NOP/阿片受体上的作用进行了药理学表征。通过用非典型氨基酸 Dmt 替代 N/OFQ（1-13）-NH 的 N 末端部分的 Tyr 和 Thr，获得了 NOP 与 mu 阿片受体效力方面的最佳结果。[Dmt]N/OFQ（1-13）-NH 已被确定为迄今为止描述的最有效的双重 NOP/mu 受体肽激动剂。实验数据通过研究补充了阐明肽结合 mu 受体活性形式的分子机制。最后，该化合物在咳嗽模型中表现出镇咳作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/146c/8279409/145d55b4aceb/jm0c02062_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/146c/8279409/9c131409e520/jm0c02062_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/146c/8279409/c49189985aff/jm0c02062_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/146c/8279409/47879438cc86/jm0c02062_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/146c/8279409/b9c301bcc591/jm0c02062_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/146c/8279409/145d55b4aceb/jm0c02062_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/146c/8279409/9c131409e520/jm0c02062_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/146c/8279409/c49189985aff/jm0c02062_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/146c/8279409/47879438cc86/jm0c02062_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/146c/8279409/b9c301bcc591/jm0c02062_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/146c/8279409/145d55b4aceb/jm0c02062_0006.jpg

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ACS Chem Neurosci. 2023 Feb 1;14(3):506-515. doi: 10.1021/acschemneuro.3c00005. Epub 2023 Jan 18.
具有强大、有效和稳定的外周给药后具有持久抗伤害作用的环阿片肽。
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