Synthesis and in Vitro Evaluation of Stabilized and Selective Neuromedin U-1 Receptor Agonists,ACS Medicinal Chemistry Letters

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Synthesis and in Vitro Evaluation of Stabilized and Selective Neuromedin U-1 Receptor Agonists
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-04-23 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00105
An De Prins _{1,

2} , Charlotte Martin ₁ , Yannick Van Wanseele ₂ , Csaba Tömböly ₃ , Dirk Tourwé ₁ , Vicky Caveliers _{4,

5} , Birgitte Holst ₆ , Ann Van Eeckhaut ₂ , Mette M. Rosenkilde ₆ , Ilse Smolders ₂ , Steven Ballet ₁

Affiliation

Neuromedin U (NMU) is a multifunctional neuropeptide which is characterized by a high conservation through all species. Herein, we describe the synthesis of a novel set of NMU-analogs based on the truncated NMU-8. Through combination of previously reported modifications, an elaborate structure–activity relationship study was performed aiming for the development of peptides with an increased selectivity toward NMU receptor 1 (NMUR1). Compound 7 possessed the highest NMUR1 selectivity (IC₅₀ = 0.54 nM, selectivity ratio = 5313) together with an increased potency (EC₅₀ = 3.7 nM), an 18% increase of the maximal effect at NMUR1, and a higher resistance against enzymatic degradation as compared to the native NMU-8. The development of a potent NMUR1 agonist with extended half-life could represent an attractive tool to further unveil the role of NMUR1 in NMU signaling.

中文翻译：

稳定和选择性Neuromedin U-1受体激动剂的合成和体外评估

Neuromedin U（NMU）是一种多功能神经肽，其特征是在所有物种中均具有较高的保守性。在这里，我们描述了基于截短的NMU-8的一组新颖的NMU-模拟物的合成。通过结合先前报道的修饰，进行了详细的结构-活性关系研究，旨在开发对NMU受体1（NMUR1）具有更高选择性的肽。化合物7具有最高的NMUR1选择性（IC ₅₀ = 0.54 nM，选择性比= 5313）以及更高的效价（EC ₅₀= 3.7 nM），与天然NMU-8相比，NMUR1的最大作用增加了18％，并且对酶促降解的抵抗力更高。具有延长的半衰期的强力NMUR1激动剂的开发可能是进一步揭示NMUR1在NMU信号传导中的作用的有吸引力的工具。

更新日期：2018-04-23

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