All-Hydrocarbon Stapled Peptide Multifunctional Agonists at Opioid and Neuropeptide FF Receptors: Highly Potent, Long-Lasting Brain Permeant Analgesics with Diminished Side Effects
All-Hydrocarbon Stapled Peptide Multifunctional Agonists at Opioid and Neuropeptide FF Receptors: Highly Potent, Long-Lasting Brain Permeant Analgesics with Diminished Side Effects
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DOI：
10.1021/acs.jmedchem.3c02093
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发表时间：
2023-12-14
影响因子：
7.3
通讯作者：
Fang，Quan
中科院分区：
文献类型：
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作者：
Zhang，Mengna;Xu，Biao;Fang，Quan
我们以前的研究报道了阿片和神经肽FF受体DN-9的多功能激动剂，沿着其环肽类似物c [D-Cys2，Cys5]-DN-9和c [D-Lys2，Asp5]-DN-9。这些类似物表现出有效的抗伤害作用，减少阿片类药物相关的副作用。为了开发更稳定、更有效的镇痛药物，我们设计、合成并评价了7个基于DN-9的环肽。体外钙动员实验表明，除3外，大部分环肽对阿片受体和神经肽FF受体均具有多功能激动活性。所有钉肽皮下给药导致有效和持久的抗伤害性活动持续长达360分钟。在这些钉肽，1a和1b出现作为优化的化合物，皮下，脑室内和口服给药后产生有效的中枢抗伤害性。此外，皮下给药1a和1b引起非耐受性抗伤害感受，便秘和成瘾的发生率有限。此外，由于1a比1b具有更宽的安全窗口，因此选择1a作为最终优化的化合物。
Our previous study reported the multifunctional agonist for opioid and neuropeptide FF receptors DN-9, along with its cyclic peptide analogues c[D-Cys2, Cys5]-DN-9 and c[D-Lys2, Asp5]-DN-9. These analogues demonstrated potent antinociceptive effects with reduced opioid-related side effects. To develop more stable and effective analgesics, we designed, synthesized, and evaluated seven hydrocarbon-stapled cyclic peptides based on DN-9.In vitrocalcium mobilization assays revealed that most of the stapled peptides, except3, displayed multifunctional agonistic activities at opioid and neuropeptide FF receptors. Subcutaneous administration of all stapled peptides resulted in effective and long-lasting antinociceptive activities lasting up to 360 min. Among these stapled peptides,1aand1bemerged as the optimized compounds, producing potent central antinociception following subcutaneous, intracerebroventricular, and oral administrations. Additionally, subcutaneous administration of1aand1bcaused nontolerance antinociception, with limited occurrence of constipation and addiction. Furthermore,1awas selected as the final optimized compound due to its wider safety window compared to1b.