Novel Synthesis and Pharmacological Characterization of NOP Receptor Agonist 8-[(1S,3aS)-2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198)
Novel Synthesis and Pharmacological Characterization of NOP Receptor Agonist 8-[(1S,3aS)-2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198)
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DOI：
10.1021/acschemneuro.5b00208
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发表时间：
2015-12-01
影响因子：
5
通讯作者：
Carroll, F. Ivy
中科院分区：
文献类型：
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作者：
Chang, Steven D.;Brieaddy, Lawrence E.;Carroll, F. Ivy
痛敏素/阿片肽（NOP）受体是一种广泛表达的GPCR，参与疼痛、焦虑和运动行为的调节。解剖这种受体的功能特性是有限的，缺乏全身活性的配体，是脑渗透。小分子NOP受体选择性完全激动剂84（1 S，3aS）-2，3，3a，4，5，6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1，3，8-triazaspiro[4.5]decan-4-one（Ro 64-6198）盐酸盐是一种活性脑渗透配体，但其合成困难且成本高昂，限制了其在动物研究中的广泛使用和可用性。在这里，我们详细介绍了一种更有效和方便的合成方法，并使用在体外和体内药理学试验，以充分表征这种配体。具体而言，我们表征了Ro 64-6198在体外cAMP和G-蛋白偶联中的药效学，并首次检查了FQ和Ro 64-6198在抑制蛋白募集测定中的痛敏肽/痛敏肽的作用。此外，我们还研究了Ro 64-6198对体内镇痛、焦虑和运动反应的影响。这种新的合成和药理学表征提供了对有用的、全身活性的NOP受体激动剂Ro 64-6198的进一步了解。
The nociceptin/orphanin FQ opioid peptide (NOP) receptor is a widely expressed GPCR involved in the modulation of pain, anxiety, and motor behaviors. Dissecting the functional properties of this receptor is limited by the lack of systemically active ligands that are brain permeant. The small molecule NOP receptor-selective, full agonist 84(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198) hydrochloride is an active, brain penetrant ligand, but its difficult and cost-prohibitive synthesis limits its widespread use and availability for animal studies. Here, we detail a more efficient and convenient method of synthesis, and use both in vitro and in vivo pharmacological assays to fully characterize this ligand. Specifically, we characterize the pharmacodynamics of Ro 64-6198 in cAMP and G-protein coupling in vitro and examine, for the first time, the effects of nociceptin/orphanin FQ and Ro 64-6198 in arrestin recruitment assays. Further, we examine the effects of Ro 64-6198 on analgesia, anxiety, and locomotor responses in vivo. This new synthesis and pharmacological characterization provide additional insights into the useful, systemically active, NOP receptor agonist Ro 64-6198.