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DEVELOPMENT OF POTENT NEUROMEDIN U RECEPTOR AGONISTS FOR REGULATING FEEDING BEHAVIOR

An De Prins1*, Charlotte Martin2, Vicky Caveliers3, Ann Van Eeckhaut1, Birgitte Holst4, Steven Ballet2 and Ilse Smolders1
  • 1 Vrije Universiteit Brussel, Pharmaceutical Chemistry and Drug Analysis, Belgium
  • 2 Vrije Universiteit Brussel, Organic Chemistry, Belgium
  • 3 Vrije Universiteit Brussel, In vivo Cellular and Molecular Imaging, Belgium
  • 4 University of Copenhagen, Molecular Pharmacology, Denmark

Diseases such as diabetes and obesity have become major health concerns worldwide. To address this issue, our group is attempting to contribute through a focus on neuromedin U (NMU), a highly conserved neuropeptide regulator of feeding, energy homeostasis and glycemic control. It exerts its biological effects via two G protein-coupled receptors, NMUR1 and NMUR2. NMUR1 is mostly found in the periphery whereas NMUR2 is most abundant in the central nervous system. Both central and pheripheral administration of the peptide reduce food intake and body weight in rodents. The anorexigenic effect of NMU renders NMUR agonists attractive as potential therapeutics in the treatment of diabetes and obesity [1]. NMU-8 (H-Tyr-Phe-Leu-Phe-Arg-Pro-Arg-Asn-NH2), a natural occurring fragment of NMU, is taken as lead molecule for the synthesis of novel analogues. A first batch of analogues is prepared on basis of the available structure-activity relationships described in the literature [2,3]. Mainly two types of modifications were initially performed, namely chirality switches and the introduction of different N-capping groups. In a second set of NMU-ligands, more advanced modifications are performed, such as the introduction of unnatural/constrained amino acids or N-alkylated glycines (‘peptoid’) analogues in the NMU-sequence. A third generation of compounds was synthesized and contains analogues in which the most promising modifications of the previous generations were combined. The in vitro characterization of these peptides has been performed by an inositol phosphate accumulation assay. Additionally, the plasma stability of these analogues has been investigated. The results of the in vitro characterization present the discovery of high potency agonists. Compared to NMU-8, more active agonists on both NMURs were discovered. Our experiments revealed, for instance, that acetylation of the N-terminus leads in general to an increase of activity. When replacing Tyr1 by 7-OH-Tic or Dmt, extremely potent agonists for both receptors were obtained as well. Moreover, an improved plasma stability of these compounds is observed. The replacement of Phe4 by 7-OH-Tic, Dmt, Oic, 1'Nal or 2'Nal leads to ligands with a comparable activity to NMU-8, but an increased plasma stability emerged. The most promising ligands were tested in an in vivo model to study their effect on food intake, and promising results were obtained. Summary: This research aims to further unveil the role of the neuropeptide neuromedin U (NMU), and more specific its function in the regulation of food intake. Since diseases like obesity and diabetes have become major health concerns, the anorexigenic effect of NMU renders NMUR agonists attractive as novel therapeutics in the treatment of obesity and diabetes. Resumé en Français: Titre: Développement de nouvelles molécules capables d’activer le récepteur de la Neuromédine pour le contrôle de la prise alimentaire. Le but de notre recherche est de mieux comprendre le rôle d’une petite molécule protéique produite par le système nerveux, la Neuromédine, dans la régulation de la prise alimentaire. Il a en effet été démontré que cette petite molécule avait des effets suppresseurs de l’appétit en agissant sur un récepteur spécifique appelé NMUR. De nouvelles molécules thérapeutiques ciblant ce récepteur NMUR pourraient permettre de lutter contre les problèmes d’obésité et de diabète. Samenvatting in het Nederlands: Titel: Studie over de invloed van ontstekingen bij hersentrauma’s. In Europa worden jaarlijks 1,4 miljoen mensen geconfronteerd met een licht hersentrauma. Deze kunnen het gevolg zijn van een val, een auto-ongeval, of ontstaan tijdens het beoefenen van een contactsport. Bij een hersentrauma ondergaan de hersenen een plotse versnelling, gevolgd door een brutale afremming. Deze snelle bewegingen van het hoofd veroorzaken letsels op het niveau van de neuronen die de hersenen vorm geven en activeren de gliale cellen, andere hersencellen die dan ontstekingsmolecules afgeven. In dit onderzoek gaat onze interesse naar de effecten van een ontstekingsmolecule, de TNF-alpha - een afsterffactor van tumoren - op de organisatie van verbindingen binnen netwerken van neuronen (synaptische plasticiteit). Onze eerste resultaten tonen aan dat enerzijds de aangroei van neuronen verbetert, maar dat anderzijds de dichtheid van de netwerken afneemt.

References

[1] Dalbøge et al, Peptides. 2015; 69: 56-65
[2] Hashimoto et al, Chem Pharm Bull. 1991; 39(9): 2319-22
[3] Takayama et al, Med Chem. 2014; 57(15): 6583-93

Keywords: neuromedin U, Obesity, peptide synthesis, inositol phoshate accumulation assay, NMUR agonists

Conference: 6th Belgian Brain Congress, MONS, Belgium, 8 Oct - 8 Oct, 2016.

Presentation Type: Poster Presentation

Topic: Brain and brain diseases: between heredity and environment

Citation: De Prins A, Martin C, Caveliers V, Van Eeckhaut A, Holst B, Ballet S and Smolders I (2016). DEVELOPMENT OF POTENT NEUROMEDIN U RECEPTOR AGONISTS FOR REGULATING FEEDING BEHAVIOR. Conference Abstract: 6th Belgian Brain Congress. doi: 10.3389/conf.fnagi.2016.03.00019

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Received: 28 Jun 2016; Published Online: 30 Jun 2016.

* Correspondence: Ms. An De Prins, Vrije Universiteit Brussel, Pharmaceutical Chemistry and Drug Analysis, Brussels, 1090, Belgium, adeprins@vub.ac.be