Structure-Based Optimization of Multifunctional Agonists for Opioid and Neuropeptide FF Receptors with Potent Nontolerance Forming Analgesic Activities
Structure-Based Optimization of Multifunctional Agonists for Opioid and Neuropeptide FF Receptors with Potent Nontolerance Forming Analgesic Activities
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基于结构的阿片类药物和神经肽 FF 受体多功能激动剂的优化，具有有效的不耐受形成镇痛活性
DOI：
10.1021/acs.jmedchem.6b01181
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发表时间：
2016
影响因子：
7.3
通讯作者：
Wang R
中科院分区：
文献类型：
--
作者：
Fang Quan;Wang Rui;Fang Q;Wang R
最近开发了含有阿片样物质和神经肽FF药效团的嵌合肽0（BN-9），并产生有效的非耐受性镇痛。本研究设计并合成了11个0的类似物。体外cAMP测定表明，这些类似物表现为阿片和NPFF受体的多功能激动剂。在小鼠甩尾实验中，大多数类似物产生强的非耐受性，形成抗伤害感受。值得注意的是，11（DN-9）的镇痛作用是0的33倍，这是由μ和κ阿片受体介导的。此外，11在福尔马林痛和CFA诱导的慢性炎性痛模型中也产生了强有力的镇痛作用。引人注目的是，在重复给药6天后，11在甩尾试验和CFA诱导的疼痛模型中没有产生抗伤害性耐受。目前的工作表明，这是合理的，设计多功能肽配体阿片和NPFF受体在一个单一的分子产生有效的非耐受性形成抗伤害感受。
The opioid and neuropeptide FF pharmacophore-containing chimeric peptide0(BN-9) was recently developed and produced potent nontolerance forming analgesia. In this study, 11 analogues of0were designed and synthesized. An in vitro cAMP assay demonstrated that these analogues behaved as multifunctional agonists at both opioid and NPFF receptors. In mouse tail-flick test, most of the analogues produced potent nontolerance forming antinociception. Notably,11(DN-9) was 33-fold more potent than0at analgesic effects, which was mediated by μ- and κ-opioid receptors. In addition,11also produced powerful analgesic effects in the formalin pain and CFA-induced chronic inflammatory pain models. Strikingly, following its repeated administration for 6 days,11did not produce antinociceptive tolerance in the tail-flick test and CFA-induced pain model. The present work indicates that it is reasonable to design multifunctional peptide ligands for opioid and NPFF receptors in a single molecule producing effective nontolerance forming antinociception.