Synthesis and in Vitro Evaluation of Stabilized and Selective Neuromedin U-1 Receptor Agonists

De Prins, An and Martin, Charlotte and Van Wanseele, Yannick and Tömböly, Csaba and Tourwé, Dirk and Caveliers, Vicky and Holst, Birgitte and Van Eeckhaut, Ann and Rosenkilde, Mette Marie and Smolders, Ilse and Ballet, Steven (2018) Synthesis and in Vitro Evaluation of Stabilized and Selective Neuromedin U-1 Receptor Agonists. ACS MEDICINAL CHEMISTRY LETTERS, 9 (5). pp. 496-501. ISSN 1948-5875

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Abstract

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.

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