title: Pharmacological characterization of lipidized analogs of prolactin-releasing peptide with a modified C- terminal aromatic ring.
abstract: 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 Phe(31) replaced by aromatic non-coded 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 PheCl2(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.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Prazienkova
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: A
authors.initials: A
authors.lastname: Ticha
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Blechova
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: A
authors.initials: A
authors.lastname: Spolcova
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: B
authors.initials: B
authors.lastname: Zelezna
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic. maletin@uochb.cas.cz.
authors.forename: L
authors.initials: L
authors.lastname: Maletinska
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D004435:Eating / Q000187:drug effects; D006801:Humans; D008055:Lipids; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000378:metabolism / Q000494:pharmacology*; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D056690:Prolactin-Releasing Hormone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D018013:Receptors, Neuropeptide / Q000378:metabolism
chemical_list: D008055:Lipids; D009479:Neuropeptides; D056690:Prolactin-Releasing Hormone; D018013:Receptors, Neuropeptide; C083929:neuropeptide FF receptor