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.

催乳素释放肽 (PrRP) 是一种厌食神经肽，可减少食物摄入并增加能量消耗。我们设计了三个系列的新脂质化 PrRP31 类似物，它们具有不同长度的脂肪酸，直接或通过接头连接在氨基酸 1 或 11 上，其中一部分在 N 末端乙酰化和/或用二氯苯丙氨酸 (PheCl ₂) 在 C 端。我们测试了它们对与受体 GPR10、NPFF-R2 和 NPFF-R1 相关的信号通路的亲和力和激活，对禁食或自由喂养的小鼠和大鼠食物摄入的影响，以及大鼠血浆中的稳定性。我们旨在选择一种强效双重 GPR10/NPFF-R2 激动剂，其对 NPFF-1 的亲和力未增强。然后，在对饮食诱导的肥胖症小鼠进行长期给药后，测试选定的有效类似物的体重降低效力。由一元羧酸脂化的 PrRP31 类似物显示出对 GPR10 和 NPFF-R2 的强双重亲和力，并在过表达 GPR10 和 NPFF-R2 的细胞中激活 MAPK/ERK1/2、Akt 和 CREB。选定的模拟物稳定在 N 和 C 末端，并通过 TTDS 连接器棕榈酰化至 Lys ¹¹是一种强大的双重激动剂 GPR10/NPFF-R2，不会增强对 NPFF-R1 的亲和力。它在饮食诱导的肥胖小鼠中显示出强烈的抗肥胖特性，并成为进一步研究的潜在化合物。