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Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure-Activity Relationship Studies.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-09 , DOI: 10.1021/acs.jmedchem.0c01376
Simon Gonzalez 1 , Maria Dumitrascuta 2 , Emilie Eiselt 3 , Stevany Louis 2 , Linda Kunze 2 , Annalisa Blasiol 2 , Mélanie Vivancos 3 , Santo Previti 1 , Elke Dewolf 1 , Charlotte Martin 1 , Dirk Tourwé 1 , Florine Cavelier 4 , Louis Gendron 3 , Philippe Sarret 3 , Mariana Spetea 2 , Steven Ballet 1
Affiliation  

Fusion of nonopioid pharmacophores, such as neurotensin, with opioid ligands represents an attractive approach for pain treatment. Herein, the μ-/δ-opioid agonist tetrapeptide H-Dmt-d-Arg-Aba-β-Ala-NH2 (KGOP01) was fused to NT(8-13) analogues. Since the NTS1 receptor has been linked to adverse effects, selective MOR-NTS2 ligands are preferred. Modifications were introduced within the native NT sequence, particularly a β3-homo amino acid in position 8 and Tyr11 substitutions. Combination of β3hArg and Dmt led to peptide 7, a MOR agonist, showing the highest NTS2 affinity described to date (Ki = 3 pM) and good NTS1 affinity (Ki = 4 nM), providing a >1300-fold NTS2 selectivity. The (6-OH)Tic-containing analogue 9 also exhibited high NTS2 affinity (Ki = 1.7 nM), with low NTS1 affinity (Ki = 4.7 μM), resulting in an excellent NTS2 selectivity (>2700). In mice, hybrid 7 produced significant and prolonged antinociception (up to 8 h), as compared to the KGOP01 opioid parent compound.

中文翻译:

优化的阿片类药物-神经降压素多靶点肽:从设计到结构-活性关系研究。

非阿片药效团(例如神经降压素)与阿片配体的融合代表了一种有吸引力的疼痛治疗方法。在此,μ-/δ-阿片激动剂四肽H-Dmt- d -Arg-Aba-β-Ala-NH 2 ( KGOP01 )与NT(8-13)类似物融合。由于 NTS1 受体与不良反应有关,因此优选选择性 MOR-NTS2 配体。在天然 NT 序列中引入修饰,特别是第 8 位的 β 3 -同型氨基酸和第11位酪氨酸取代。β 3 hArg 和 Dmt 的组合产生肽7,一种 MOR 激动剂,显示出迄今为止描述的最高 NTS2 亲和力 ( K i = 3 pM) 和良好的 NTS1 亲和力 ( K i = 4 nM),提供 >1300 倍的 NTS2选择性。含有 (6-OH)Tic 的类似物9还表现出高 NTS2 亲和力 ( K i = 1.7 nM) 和低 NTS1 亲和力 ( K i = 4.7 μM),从而产生优异的 NTS2 选择性 (>2700)。在小鼠中,与KGOP01阿片类母体化合物相比, Hybrid 7产生显着且持久的镇痛作用(长达 8 小时) 。
更新日期:2020-11-12
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