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新型非偏向性阿片受体（NOP）选择性非肽激动剂AT-403的体外药理学特性研究

In vitro pharmacological characterization of a novel unbiased NOP receptor-selective nonpeptide agonist AT-403.

作者信息

Ferrari Federica, Malfacini Davide, Journigan Blair V, Bird Mark F, Trapella Claudio, Guerrini Remo, Lambert David G, Calo' Girolamo, Zaveri Nurulain T

机构信息

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

Astraea Therapeutics, LLC. 320 Logue Avenue, Mountain View, California.

出版信息

Pharmacol Res Perspect. 2017 Aug;5(4). doi: 10.1002/prp2.333.

DOI:10.1002/prp2.333
PMID:28805972
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5684865/
Abstract

Nociceptin/orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP), a member of the opioid receptor family. We recently identified a new high affinity and highly selective NOP agonist AT-403. In this study, we characterized the functional profile of AT-403 and compared it to other known nonpeptide NOP agonists Ro 65-6570, Ro 2q, SCH-221510, MCOPPB, AT-202 and SCH-486757, using the following assays: GTPγ[ S] stimulated binding, calcium mobilization assay in cells-expressing human NOP or classical opioid receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, and the electrically stimulated mouse vas deferens bioassay. All compounds behaved as NOP full agonists consistently showing the following rank order of potency MCOPPB > AT-403 > Ro 65-6570 = Ro 2q > SCH-221510 >  AT-202 > SCH-486757. AT-403 and MCOPPB displayed the highest NOP selectivity both at human and murine receptors. Interestingly, while all the other nonpeptide NOP agonists displayed bias toward G protein-mediated signaling in the BRET assay, AT-403, similar to the natural ligand N/OFQ, behaved as an unbiased agonist, activating G-protein-mediated function as well as arrestin recruitment. AT-403 may be a useful nonpeptide tool compound to study the pharmacology of NOP activation in disease states.

摘要

痛敏肽/孤啡肽FQ（N/OFQ）通过选择性激活阿片受体家族成员N/OFQ受体（NOP）来调节多种生物学功能。我们最近鉴定出一种新型高亲和力和高选择性的NOP激动剂AT-403。在本研究中，我们对AT-403的功能特性进行了表征，并将其与其他已知的非肽类NOP激动剂Ro 65-6570、Ro 2q、SCH-221510、MCOPPB、AT-202和SCH-486757进行了比较，采用了以下实验：GTPγ[ S]刺激结合实验、在表达人NOP或经典阿片受体及嵌合G蛋白的细胞中进行钙动员实验、基于生物发光共振能量转移（BRET）的实验以研究NOP受体与G蛋白和抑制蛋白的相互作用，以及电刺激小鼠输精管生物测定实验。所有化合物均表现为NOP完全激动剂，始终呈现出以下效价顺序：MCOPPB > AT-403 > Ro 65-6570 = Ro 2q > SCH-221510 > AT-202 > SCH-486757。AT-403和MCOPPB在人和小鼠受体上均表现出最高的NOP选择性。有趣的是，虽然所有其他非肽类NOP激动剂在BRET实验中对G蛋白介导的信号传导表现出偏向性，但AT-403与天然配体N/OFQ相似，表现为无偏向性激动剂，既能激活G蛋白介导的功能，又能促进抑制蛋白的募集。AT-403可能是一种有用的非肽类工具化合物，用于研究疾病状态下NOP激活的药理学。

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