Search for lipidized PrRP analogs with strong anorexigenic effect: In vitro and in vivo studies

• Published in: Neuropeptides (Edinburgh) 2023-04, Vol.98, p.102319-102319, Article 102319
• Main Authors: Strnadová, Veronika, Karnošová, Alena, Blechová, Miroslava, Neprašová, Barbora, Holá, Lucie, Němcová, Anna, Myšková, Aneta, Sýkora, David, Železná, Blanka, Kuneš, Jaroslav, Maletínská, Lenka
• Format: Article
• Language: English
• Subjects: Akt activation; Animals; Diet; ERK; Fatty Acids; Food intake; GPR10; Lipidization; Mice; Neuropeptides; NPFF-R1; NPFF-R2; Obesity - drug therapy; Obesity - metabolism; Prolactin-Releasing Hormone - metabolism; Prolactin-Releasing Hormone - pharmacology; Prolactin-releasing peptide; Rats; Stability
• ISSN: 0143-4179; 1532-2785
• DOI: 10.1016/j.npep.2022.102319

Prolactin-releasing peptide (PrRP) is an anorexigenic neuropeptide that attenuates food intake and increases energy expenditure. We designed three series of new lipidized PrRP31 analogs of different lengths of fatty acids attached at amino acids 1 or 11 directly or via linkers, part of them acetylated at the N-terminus and/or modified with dichlorophenylalanine (PheCl2) at the C-terminus. We tested their affinity for and activation of signaling pathways relevant to receptors GPR10, NPFF-R2, and NPFF-R1, effect on food intake in fasted or freely fed mice and rats, and stability in rat plasma. We aimed to select a strong dual GPR10/NPFF-R2 agonist whose affinity for NPFF-1 was not enhanced. The selected potent analog was then tested for body weight-lowering potency after chronic administration in mice with diet-induced obesity. PrRP31 analogs lipidized by monocarboxylic fatty acids showed strong dual affinity for both GPR10 and NPFF-R2 and activated MAPK/ERK1/2, Akt and CREB in cells overexpressing GPR10 and NPFF-R2. The selected analog stabilized at N- and C-termini and palmitoylated through the TTDS linker to Lys11 is a powerful dual agonist GPR10/NPFF-R2 at not enhanced affinity for NPFF-R1. It showed strong anti-obesity properties in mice with diet-induced obesity and became a potential compound for further studies. •Palmitoylated PrRP31 analogs show strong affinity for GPR10 and NPFF-R2 receptors.•These lipidized PrRP31 analogs have a strong anorexigenic effect.•PrRP31 analogs with hexadecanedioic acid have lowered affinity and in vivo potency.•The most potent analog revealed strong anti-obesity properties.•Dual GPR10/NPFF-R2 agonism is needed for anorexigenic effect