Discovery of κ Opioid Receptor (KOR)-Selective d-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration.
Discovery of κ Opioid Receptor (KOR)-Selective d-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration.
复制标题
发现 γ 阿片受体 (KOR)-选择性 d-四肽，在外周给药后具有改善的体内抗伤害作用。
DOI：
10.1021/acsmedchemlett.2c00237
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发表时间：
2022
影响因子：
4.2
通讯作者：
Streicher,J
中科院分区：
文献类型：
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作者：
Stefanucci,Azzurra;DellaValle,Alice;Scioli,Giuseppe;Marinaccio,Lorenza;Pieretti,Stefano;Minosi,Paola;Szucs,Edina;Benyhe,Sandor;Masci,Domiziana;Tanguturi,Parthasaradhireddy;Chou,Kerry;Barlow,Deborah;Houseknecht,Karen;Streicher,J
采用Fmoc保护策略固相合成κ阿片受体激动剂，以较高的纯度和总收率合成了具有外周活性的四肽类化合物。在前导化合物FF(d-NLE)R-NH2(FE200041)的第一位和第二位进行了结构修饰，其中含有d-氨基酸的芳香族侧链，如(D)-PF-Phe，(D)-MF-Phe，(D)-Of-Phe，使得KOR激动剂在静脉注射后具有很强的抗伤害性活性。和皮下(S.C.)管理人员在摇尾巴和福尔马林测试。这些结果提示在治疗神经病理性和炎症性疼痛方面具有潜在的临床应用价值。
Peripherally active tetrapeptides as selective κ opioid receptor (KOR) agonists have been prepared in good overall yields and high purity following solid-phase peptide synthesis via Fmoc protection strategy. Structural modifications at the first and second position of thelead compoundFF(d-Nle)R-NH2(FE200041) were contemplated with aromatic side chains containingd-amino acids, such as (d)-pF-Phe, (d)-mF-Phe, (d)-oF-Phe, which led to highly selective and efficacious KOR agonists endowed with strong antinociceptive activityin vivofollowing intravenous (i.v.) and subcutaneous (s.c.) administration in the tail flick and formalin tests. These results suggest potential clinical applications in the treatment of neuropathic and inflammatory pain.