Development of Multifunctional and Orally Active Cyclic Peptide Agonists of Opioid/Neuropeptide FF Receptors that Produce Potent, Long-Lasting, and Peripherally Restricted Antinociception with Diminished Side Effects
Development of Multifunctional and Orally Active Cyclic Peptide Agonists of Opioid/Neuropeptide FF Receptors that Produce Potent, Long-Lasting, and Peripherally Restricted Antinociception with Diminished Side Effects
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开发阿片类/神经肽 FF 受体的多功能口服活性环肽激动剂，可产生有效、持久、外周受限的镇痛作用，并减少副作用
DOI：
10.1021/acs.jmedchem.1c00694
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发表时间：
2021
影响因子：
7.3
通讯作者：
Fang Quan
中科院分区：
文献类型：
--
作者：
Zhang Mengna;Xu Biao;Li Ning;Zhang Run;Zhang Qinqin;Shi Xuerui;Xu Kangtai;Xiao Jian;Chen Dan;Niu Ji;ong;Shi Yonghang;Fang Quan
我们之前报道过一种多功能阿片类/神经肽 FF 受体激动剂 DN-9，可实现外周限制性镇痛并减少副作用。为了开发稳定且可口服生物利用的 DN-9 类似物，设计、合成了 8 个 DN-9 位点 2 和 5 之间的内酰胺桥环状类似物，并进行了生物学评估。 体外 cAMP 测定表明，除 7 之外，这些类似物是激活阿片类药物和神经肽 FF 受体的多功能配体。类似物 1 对 κ-阿片类药物和 NPFF2 受体表现出增强的效力。所有类似物在甩尾试验中均表现出强效、持久且外周受限的抗伤害作用，皮下给药后未出现耐受性，并产生口服镇痛作用。口服优化的化合物类似物1在急性、炎症和神经性疼痛的小鼠模型中表现出强大的、外周限制的抗伤害作用。值得注意的是，口服类似物1在有效镇痛剂量下没有明显的副作用，例如耐受性、依赖性、便秘或呼吸抑制。
We previously reported that a multifunctional opioid/neuropeptide FF receptor agonist, DN-9, achieved peripherally restricted analgesia with reduced side effects. To develop stable and orally bioavailable analogues of DN-9, eight lactam-bridged cyclic analogues of DN-9 between positions 2 and 5 were designed, synthesized, and biologically evaluated.In vitrocAMP assays revealed that these analogues, except7, were multifunctional ligands that activated opioid and neuropeptide FF receptors. Analogue1exhibited improved potency for κ-opioid and NPFF2receptors. All analogues exhibited potent, long-lasting, and peripherally restricted antinociception in the tail-flick test without tolerance development after subcutaneous administration and produced oral analgesia. Oral administration of the optimized compound analogue1exhibited powerful, peripherally restricted antinociceptive effects in mouse models of acute, inflammatory, and neuropathic pain. Remarkably, orally administered analogue1had no significant side effects, such as tolerance, dependence, constipation, or respiratory depression, at effective analgesic doses.