1. Synthesis and in Vitro Evaluation of Stabilized and Selective Neuromedin U-1 Receptor Agonists
- Author
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Ann Van Eeckhaut, Charlotte Martin, Birgitte Holst, Ilse Julia Smolders, An De Prins, Vicky Caveliers, Mette M. Rosenkilde, Csaba Tömböly, Yannick Van Wanseele, Dirk Tourwé, Steven Ballet, Faculty of Medicine and Pharmacy, Experimental Pharmacology, Chemistry, WE Academic Unit, Vriendenkring VUB, High Resolution NMR Centre, Organic Chemistry, Translational Imaging Research Alliance, Medical Imaging, Supporting clinical sciences, Nuclear Medicine, Pharmaceutical and Pharmacological Sciences, and Alliance for Modulation in Epilepsy
- Subjects
0301 basic medicine ,Agonist ,medicine.drug_class ,Stereochemistry ,in vitro plasma stability ,Neuromedin U receptor agonist ,Neuropeptide ,Neuromedin U (NMU) ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,Drug Discovery ,medicine ,Receptor ,IC50 ,EC50 ,010405 organic chemistry ,Chemistry ,NMU-8 ,Organic Chemistry ,In vitro ,0104 chemical sciences ,NMUR1 ,030104 developmental biology ,Selectivity ,Neuromedin U - 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 (IC 50 = 0.54 nM, selectivity ratio = 5313) together with an increased potency (EC 50 = 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.
- Published
- 2018