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新型镇痛药塞布诺帕多的药理学特性：一种兼具孤啡肽/痛敏肽和阿片受体激动剂作用的混合性药物

Pharmacological characterization of cebranopadol a novel analgesic acting as mixed nociceptin/orphanin FQ and opioid receptor agonist.

作者信息

Rizzi Anna, Cerlesi Maria Camilla, Ruzza Chiara, Malfacini Davide, Ferrari Federica, Bianco Sara, Costa Tommaso, Guerrini Remo, Trapella Claudio, Calo' Girolamo

机构信息

Department of Medical Sciences Section of Pharmacology and National Institute of Neuroscience University of Ferrara Ferrara Italy.

Department of Chemical and Pharmaceutical Sciences and LTTA University of Ferrara Ferrara Italy.

出版信息

Pharmacol Res Perspect. 2016 Aug 2;4(4):e00247. doi: 10.1002/prp2.247. eCollection 2016 Aug.

DOI:10.1002/prp2.247
PMID:28116100
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5242173/
Abstract

The aim of the study was to investigate the in vitro and in vivo pharmacological profile of cebranopadol, a novel agonist for opioid and nociceptin/orphanin FQ (N/OFQ) receptors (NOP). In vitro cebranopadol was assayed in calcium mobilization studies in cells coexpressing NOP or opioid receptors and chimeric G-proteins and in a bioluminescence resonance energy transfer (BRET) assay for studying receptor interaction with G-protein and -arrestin 2. The mouse tail withdrawal and formalin tests were used for investigating cebranopadol antinociceptive properties. In calcium mobilization studies cebranopadol showed the following rank order of potency NOP = mu > kappa ≥ delta. In BRET studies, cebranopadol promoted NOP and mu receptors interaction with G-protein with similar high potency and efficacy. However, cebranopadol did not stimulated NOP--arrestin 2 interactions and displayed reduced potency at mu/-arrestin 2. In vivo, cebranopadol exhibits highly potent and extremely long-lasting antinociceptive effects. The effects of cebranopadol in the tail withdrawal assay were sensitive to both SB-612111 and naloxone. Collectively the present results confirm and extend previous finding demonstrating that cebranopadol, by acting as mixed NOP/opioid receptor agonist, elicits robust analgesic effects in different pain models.

摘要

本研究旨在探究cebranopadol的体外和体内药理学特性，cebranopadol是一种新型的阿片类和孤啡肽/孤啡肽FQ（N/OFQ）受体（NOP）激动剂。在体外，cebranopadol在共表达NOP或阿片类受体及嵌合G蛋白的细胞的钙动员研究中进行了检测，并在生物发光共振能量转移（BRET）试验中用于研究受体与G蛋白及β-抑制蛋白2的相互作用。小鼠甩尾试验和福尔马林试验用于研究cebranopadol的抗伤害感受特性。在钙动员研究中，cebranopadol显示出以下效价顺序：NOP = μ＞κ≥δ。在BRET研究中，cebranopadol促进NOP和μ受体与G蛋白的相互作用，效力和效能相似且都很高。然而，cebranopadol未刺激NOP与β-抑制蛋白2的相互作用，且在μ/β-抑制蛋白2处的效力降低。在体内，cebranopadol表现出高效且极其持久的抗伤害感受作用。cebranopadol在甩尾试验中的作用对SB - 612111和纳洛酮均敏感。总体而言，目前的结果证实并扩展了先前的发现，表明cebranopadol作为NOP/阿片类受体混合激动剂，在不同疼痛模型中引发强大的镇痛作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6484/5242173/79a8a0b6a5da/PRP2-4-0247-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6484/5242173/8961e710e07e/PRP2-4-0247-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6484/5242173/7f2c11c9e00b/PRP2-4-0247-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6484/5242173/79a8a0b6a5da/PRP2-4-0247-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6484/5242173/3e25ab1bd463/PRP2-4-0247-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6484/5242173/b043b2f34130/PRP2-4-0247-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6484/5242173/bc843899f1aa/PRP2-4-0247-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6484/5242173/4908248d6b57/PRP2-4-0247-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6484/5242173/737e31c2c810/PRP2-4-0247-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6484/5242173/8961e710e07e/PRP2-4-0247-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6484/5242173/7f2c11c9e00b/PRP2-4-0247-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6484/5242173/79a8a0b6a5da/PRP2-4-0247-g010.jpg

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