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

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 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. © 2016,polish physiological society. all right reserved.