Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62., H-6726 Szeged, Hungary.
Doctoral School of Theoretical Medicine, Faculty of Medicine, University of Szeged, Dómtér 10, H-6720 Szeged, Hungary.
Biomolecules. 2020 Feb 12;10(2):284. doi: 10.3390/biom10020284.
Kynurenine (kyn) and kynurenic acid (kyna) are well-defined metabolites of tryptophan catabolism collectively known as "kynurenines", which exert regulatory functions in host-microbiome signaling, immune cell response, and neuronal excitability. Kynurenine containing peptides endowed with opioid receptor activity have been isolated from natural organisms; thus, in this work, novel opioid peptide analogs incorporating L-kynurenine (L-kyn) and kynurenic acid (kyna) in place of native amino acids have been designed and synthesized with the aim to investigate the biological effect of these modifications. The kyna-containing peptide () binds selectively the m-opioid receptor with a Ki = 1.08 ± 0.26 (selectivity ratio m/d/k = 1:514:10000), while the L-kyn-containing peptide () shows a mixed binding affinity for m, d, and k-opioid receptors, with efficacy and potency (E = 209.7 + 3.4%; LogEC = -5.984 + 0.054) higher than those of the reference compound DAMGO. This novel oligopeptide exhibits a strong antinociceptive effect after i.c.v. and s.c. administrations in in vivo tests, according to good stability in human plasma (t = 47 min).
犬尿氨酸（kyn）和犬尿烯酸（kyna）是色氨酸分解代谢的明确代谢产物，统称为“犬尿氨酸”，它们在宿主-微生物群信号、免疫细胞反应和神经元兴奋性中发挥调节作用。从天然生物中分离出具有阿片受体活性的含犬尿氨酸的肽；因此，在这项工作中，设计并合成了含有 L-犬尿氨酸（L-kyn）和犬尿烯酸（kyna）取代天然氨基酸的新型阿片肽类似物，目的是研究这些修饰的生物学效应。含有 kyna 的肽 () 选择性地与 m-阿片受体结合，Ki = 1.08 ± 0.26（选择性比率 m/d/k = 1:514:10000），而含有 L-kyn 的肽 () 对 m、d 和 k-阿片受体表现出混合结合亲和力，效力和效能 (E = 209.7 + 3.4%；LogEC = -5.984 + 0.054) 均高于参考化合物 DAMGO。根据在体内试验中 i.c.v. 和 s.c. 给药后的强烈镇痛作用，这种新型寡肽在人血浆中具有良好的稳定性（t = 47 min）。
