化学
药效团
类阿片
药理学
止痛药
兴奋剂
受体
生物活性
伤害
立体化学
结构-活动关系
体外
生物化学
医学
作者
Qinqin Zhang,Biao Xu,Dan Chen,Shoujun Wu,Xuanran Hu,Xiaodi Zhang,Bowen Yu,Chengqi Zhang,Zhiyuan Yang,Mengna Zhang,Quan Fang
标识
DOI:10.1021/acs.jmedchem.3c01347
摘要
The cyclic peptide c[d-Lys2, Asp5]-DN-9 has recently been identified as a multifunctional opioid/neuropeptide FF receptor agonist, displaying potent analgesic activity with reduced side effects. This study utilized Tyr-c[d-Lys-Gly-Phe-Asp]-d-Pro-NH2 (0), a cyclic hexapeptide derived from the opioid pharmacophore of c[d-Lys2, Asp5]-DN-9, as a chemical template. We designed, synthesized, and characterized 22 analogs of 0 with a single amino acid substitution to investigate its structure-activity relationship. Most of these cyclic hexapeptide analogs exhibited multifunctional activity at μ and δ opioid receptors (MOR and DOR, respectively) and produced antinociceptive effects following subcutaneous administration. The lead compound analog 15 showed potent agonistic activities at the MOR, κ opioid receptor (KOR), and DOR in vitro and produced a strong and long-lasting analgesic effect through peripheral MOR and KOR in the tail-flick test. Further biological evaluation identified that analog 15 did not cause significant side effects such as tolerance, withdrawal, or reward liability.
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