Junwei Zhao, Monica Baiula, Elisabetta Cuna, Marco Francescato, Joanna Matalińska, Piotr F.J. Lipiński, Andrea Bedini, Luca Gentilucci
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引用次数: 0
摘要
最近，真菌次生代谢物环四肽 c[Trp-Phe-D-Pro-Phe] （CJ-15,208）及其衍生物因其不同寻常的结构和独特的体内外活性而备受关注。这些含色氨酸的非阳离子类阿片肽可被真正视为能激活所有阿片受体的多功能螯合剂。有趣的是，对强效κ-阿片受体（KOR）激动剂c[D-Trp-Phe-Gly-β-Ala] (3)进行最小化修饰后，产生了c[D-Trp-Phe-β-Ala-β-Ala] (11)，这是迄今为止报道的首个KOR特异性负异调节剂（NAM）。KOR 可控制中枢神经系统的多种功能，包括疼痛、抑郁、压力、情绪和奖赏。因此，这种 KOR 选择性 NAM 对于调节成瘾和神经精神疾病中的 KOR 很有希望。
Identification of c[D-Trp-Phe-β-Ala-β-Ala], the First κ-Opioid Receptor-Specific Negative Allosteric Modulator
Recently, the fungus secondary metabolite cyclotetrapetide c[Trp-Phe-D-Pro-Phe] (CJ-15,208) and its derivatives deserved some attention for their unusual structure and distinctive in vitro and in vivo activity. These tryptophan-containing noncationic opioid peptides can be truly regarded as versatile picklocks capable of activating all opioid receptors. Intriguingly, minimal modification of the potent κ-opioid receptor (KOR) agonist c[D-Trp-Phe-Gly-β-Ala] (3) yielded c[D-Trp-Phe-β-Ala-β-Ala] (11), the first KOR-specific negative allosteric modulator (NAM) reported to-date. KOR exerts control over numerous functions in the central nervous system, including pain, depression, stress, mood, and reward. Hence, this KOR-selective NAM looks promising for modulating the KOR in addiction and neuropsychiatric disorders.
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