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

An De Prins; Charlotte Martin; Yannick Van Wanseele; Csaba Tömböly; Dirk Tourwé; Vicky Caveliers; Birgitte Holst; Ann Van Eeckhaut; Mette M Rosenkilde; Ilse Smolders; Steven Ballet

doi:10.1021/acsmedchemlett.8b00105

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

An De Prins, Charlotte Martin, Yannick Van Wanseele, Csaba Tömböly, Dirk Tourwé, Vicky Caveliers, Birgitte Holst, Ann Van Eeckhaut, Mette M Rosenkilde, Ilse Smolders, Steven Ballet

4 Citations (Scopus)

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.

Original language	English
Journal	ACS Medicinal Chemistry Letters
Volume	9
Issue number	5
Pages (from-to)	496-501
Number of pages	6
ISSN	1948-5875
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00105
Publication status	Published - 10 May 2018

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title = "Synthesis and in Vitro Evaluation of Stabilized and Selective Neuromedin U-1 Receptor Agonists",

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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year = "2018",

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doi = "10.1021/acsmedchemlett.8b00105",

language = "English",

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pages = "496--501",

journal = "ACS Medicinal Chemistry Letters",

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T1 - Synthesis and in Vitro Evaluation of Stabilized and Selective Neuromedin U-1 Receptor Agonists

AU - De Prins, An

AU - Martin, Charlotte

AU - Van Wanseele, Yannick

AU - Tömböly, Csaba

AU - Tourwé, Dirk

AU - Caveliers, Vicky

AU - Holst, Birgitte

AU - Van Eeckhaut, Ann

AU - Rosenkilde, Mette M

AU - Smolders, Ilse

AU - Ballet, Steven

PY - 2018/5/10

Y1 - 2018/5/10

N2 - 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.

AB - 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.

U2 - 10.1021/acsmedchemlett.8b00105

DO - 10.1021/acsmedchemlett.8b00105

M3 - Journal article

C2 - 29795766

SN - 1948-5875

VL - 9

SP - 496

EP - 501

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 5

ER -

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

Abstract

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