Pharmacological characterization of lipidized analogs of prolactin-releasing peptide with a modified C-terminal aromatic ring

0459379 - ÚOCHB 2017 RIV PL eng J - Journal Article
Pražienková, Veronika - Tichá, Anežka - Blechová, Miroslava - Špolcová, Andrea - Železná, Blanka - Maletínská, Lenka
Pharmacological characterization of lipidized analogs of prolactin-releasing peptide with a modified C-terminal aromatic ring.
Journal of Physiology and Pharmacology. Roč. 67, č. 1 (2016), s. 121-128. ISSN 0867-5910
R&D Projects: GA ČR(CZ) GA15-08679S
Institutional support: RVO:61388963
Keywords : prolactin-releasing peptide * blood-brain barrier * food intake * lipidization * phenylalanine derivatives
Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition
Impact factor: 2.883, year: 2016
http://www.jpp.krakow.pl/journal/archive/02_16/articles/11_article.html

Prolactin-releasing peptide (PrRP) is an anorexigenic neuropeptide expressed in the brain where it regulates food intake and energy expenditure. The C-terminal Arg-Phe-NH2 of PrRP is crucial for its biological activity. In our previous study, we showed that PrRP analogs myristoylated or palmitoylated at the N-terminus seem to cross the blood-brain barrier and lower food intake following peripheral administration. In this study, myristoylated and palmitoylated PrRP31 analogs with a modified C-terminal Phe were designed and tested. Lipidized analogs containing Phe31 replaced by aromatic noncoded amino acids or tyrosine revealed high binding affinity to rat pituitary RC-4B/C cells with endogenous PrRP and neuropeptide FF 2 receptors and to CHO-K1 cells overexpressing either PrRP or neuropeptide FF 2 receptors. The analogs also showed strong agonistic properties at the GPR10 receptor using the beta-lactamase reporter gene assay. Moreover, lipidized PrRP analogs, especially those that were palmitoylated, demonstrated strong and long-lasting anorexigenic effects in fasted mice after subcutaneous administration. The most efficient PrRP31 analogs with PheCl(2)(31), either palmitoylated or myristoylated at the N-terminus, are promising candidates for the study of food disorders, possibly for anti-obesity treatment. Despite the therapeutic potential in targeting central GPR10, the endogenous ligand PrRP cannot cross the blood-brain barrier. Understanding biological activity and transport of novel structural analogs of PrRP with a potential central anorexigenic effect is of key therapeutic significance.
Permanent Link: http://hdl.handle.net/11104/0259583