Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy (F.F., S.R., C.R., G.C.) and Technopole of Ferrara, LTTA Laboratory for Advanced Therapies, Ferrara, Italy (C.R.).
Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy (F.F., S.R., C.R., G.C.) and Technopole of Ferrara, LTTA Laboratory for Advanced Therapies, Ferrara, Italy (C.R.)
J Pharmacol Exp Ther. 2020 Apr;373(1):34-43. doi: 10.1124/jpet.119.262865. Epub 2020 Jan 14.
The peptide nociceptin/orphanin FQ (N/OFQ) is the natural ligand of the N/OFQ receptor (NOP), which is widely expressed in the central and peripheral nervous system. Selective NOP antagonists are worthy of testing as innovative drugs to treat depression, Parkinson disease, and drug abuse. The aim of this study was to perform a detailed in vitro characterization of BTRX-246040 (also known as LY2940094, [2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol), a novel NOP antagonist that has been already studied in humans. BTRX-246040 has been tested in vitro in the following assays: calcium mobilization in cells expressing NOP and classic opioid receptors and chimeric G proteins, bioluminescence resonance energy transfer assay measuring NOP interaction with G proteins and -arrestins, the label-free dynamic mass redistribution assay, and the electrically stimulated mouse vas deferens. BTRX-246040 was systematically compared with the standard NOP antagonist SB-612111. In all assays, BTRX-246040 behaves as a pure and selective antagonist at human recombinant and murine native NOP receptors displaying 3-10-fold higher potency than the standard antagonist SB-612111. BTRX-246040 is an essential pharmacological tool to further investigate the therapeutic potential of NOP antagonists in preclinical and clinical studies. SIGNIFICANCE STATEMENT: NOP antagonists may be innovative antidepressant drugs. In this research, the novel clinically viable NOP antagonist BTRX-246040 has been deeply characterized in vitro in a panel of assays. BTRX-246040 resulted a pure, potent, and selective NOP antagonist.
孤啡肽（Nociceptin/Orphanin FQ，N/OFQ）是 N/OFQ 受体（NOP）的天然配体，该受体广泛表达于中枢和外周神经系统。选择性 NOP 拮抗剂有望成为治疗抑郁症、帕金森病和药物滥用的创新药物进行测试。本研究旨在对新型 NOP 拮抗剂 BTRX-246040（也称为 LY2940094，[2-[4-[(2-氯-4,4-二氟螺[5H-噻吩并[2,3-c]吡喃-7,4'-哌啶]-1'-基]甲基]-3-甲基-吡唑-1-基]-3-吡啶基]甲醇）进行详细的体外特征分析，该拮抗剂已在人体中进行了研究。BTRX-246040 已在以下测定中进行了体外测试：表达 NOP 和经典阿片受体和嵌合 G 蛋白的细胞中的钙动员、测量 NOP 与 G 蛋白和 -arrestin 相互作用的生物发光共振能量转移测定、无标记动态质量重分布测定和电刺激的小鼠输精管。BTRX-246040 与标准 NOP 拮抗剂 SB-612111 进行了系统比较。在所有测定中，BTRX-246040 作为人重组和鼠天然 NOP 受体的纯和选择性拮抗剂起作用，对标准拮抗剂 SB-612111 的效力高 3-10 倍。BTRX-246040 是进一步研究 NOP 拮抗剂在临床前和临床研究中的治疗潜力的重要药理学工具。
NOP 拮抗剂可能是创新的抗抑郁药物。在这项研究中，新型临床可行的 NOP 拮抗剂 BTRX-246040 在一系列测定中进行了深入的体外特征分析。BTRX-246040 是一种纯、有效和选择性的 NOP 拮抗剂。
