Development and in vitro characterization of Neuromedin U analogues
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1
Vrije Universiteit Brussel, Dept. of Pharmaceutical Chemistry and Drug Analysis, Belgium
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2
Vrije Universiteit Brussel, Dept. of Organic Chemistry, Belgium
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3
University of Copenhagen, Dept. of Neuroscience and Pharmacology, Denmark
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4
Vrije Universiteit Brussel, Dept. of In vivo Cellular and Molecular Imaging, Belgium
Chronic stress is a predominant risk factor for a variety of psychiatric and neurological disorders such as depression, anxiety and epilepsy (1). Endogenous systems which regulate the stress response are interesting targets for the development of novel treatments for these stress-related disorders. In this study we focus on neuromedin U (NMU), a neuropeptide regulator of the stress response via top-down control of the hypothalamus-pituitary-adrenal axis. NMU exerts its biological effects via two G protein-coupled receptors, NMUR1 and NMUR2. NMUR1 is mostly found in the periphery whereas NMUR2, the receptor of our interest, is most abundant in the central nervous system (2). The purpose of this study is to develop new peptidergic selective NMUR2 antagonists which are enzymatically stable and blood-brain-barrier (BBB) permeable.
NMU-8, a natural occurring form of NMU, is taken as lead molecule for the synthesis of new analogues. The NMU-ligands are synthesized via solid phase peptide synthesis under classical conditions on rink amide polystyrene resin. A first batch of analogues is prepared on basis of the available structure-activity relationships. The in vitro characterization of these peptides is performed by an inositol phosphate accumulation assay.
The results of this in vitro characterization are generally in line with the available literature. EC50 values of a similar magnitude are found for NMU-8. Moreover our experiments revealed that acetylation of the N-terminus leads in general to an increase of the relative activity compared to the non-acetylated ligand. In conclusion, further research is needed to synthesize a NMUR2 selective, enzymatically stable and BBB permeable ligand.
Acknowledgements
This research is supported by the Agency for Innovation by Science and Technology in Flanders (IWT)
References
(1) Joels et al., Pharmacol Rev, 2012, 64(4): 901-38
(2) Brighton et al., Pharmacol Rev, 2004, 56(2): 231-48
Keywords:
neuromedin U,
Depression,
Anxiety Disorders,
Epilepsy,
In vitro characterization,
Peptide synthesis.
Conference:
11th National Congress of the Belgian Society for Neuroscience, Mons, Belgium, 22 May - 22 May, 2015.
Presentation Type:
Poster presentation
Topic:
Neuroscience
Citation:
De Prins
A,
Betti
C,
Sivertsen
B,
Caveliers
V,
Van Eeckhaut
A,
Holst
B,
Ballet
S and
Smolders
IJ
(2015). Development and in vitro characterization of Neuromedin U analogues.
Front. Neurosci.
Conference Abstract:
11th National Congress of the Belgian Society for Neuroscience.
doi: 10.3389/conf.fnins.2015.89.00047
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Received:
29 Apr 2015;
Published Online:
05 May 2015.
*
Correspondence:
Miss. An De Prins, Vrije Universiteit Brussel, Dept. of Pharmaceutical Chemistry and Drug Analysis, Brussels, 1090, Belgium, adeprins@vub.ac.be