化学
类阿片
药理学
兴奋剂
受体
神经肽
止痛药
伤害
肽
生物化学
医学
作者
Mengna Zhang,Biao Xu,Ning Li,Qinqin Zhang,Dan Chen,Shoujun Wu,Bowen Yu,Xiaodi Zhang,Xuanran Hu,Chengqi Zhang,Yu‐Hong Jing,Zhiyuan Yang,Jinhong Jiang,Quan Fang
标识
DOI:10.1021/acs.jmedchem.3c02093
摘要
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 vitro calcium mobilization assays revealed that most of the stapled peptides, except 3, 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, 1a and 1b emerged as the optimized compounds, producing potent central antinociception following subcutaneous, intracerebroventricular, and oral administrations. Additionally, subcutaneous administration of 1a and 1b caused nontolerance antinociception, with limited occurrence of constipation and addiction. Furthermore, 1a was selected as the final optimized compound due to its wider safety window compared to 1b.
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