The family of neuropeptide Y (NPY) receptors comprises four subtypes (Y₁R, Y₂R, Y₄R, Y₅R), which are addressed by at least three endogenous peptides, i.e., NPY, peptide YY, and pancreatic polypeptide (PP), the latter showing a preference for Y₄R. A series of cyclic oligopeptidic Y₄R ligands were prepared by applying a novel approach, i.e., N-terminus to arginine side-chain cyclization. Most peptides acted as Y₄R partial agonists, showing up to 60-fold higher Y₄R affinity compared to the linear precursor peptides. Two cyclic hexapeptides (18, 24) showed higher Y₄R potency (Ca²⁺ aequorin assay) and, with pK_i values >10, also higher Y₄R affinity compared to human pancreatic polypeptide (hPP). Compounds such as 18 and 24, exhibiting considerably lower molecular weight and considerably more pronounced Y₄R selectivity than PP and previously described dimeric peptidic ligands with high Y₄R affinity, represent promising leads for the preparation of labeled tool compounds and might support the development of drug-like Y₄R ligands.

中文翻译：

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线性肽神经肽 Y Y4 受体配体的 N 末端到精氨酸侧链环化导致皮摩尔结合常数

神经肽 Y (NPY) 受体家族包含四种亚型（Y ₁ R、Y ₂ R、Y ₄ R、Y ₅ R），它们由至少三种内源性肽（即 NPY、肽 YY 和胰多肽）处理(PP)，后者显示出对Y ₄ R 的偏好。一系列环状寡肽Y ₄ R 配体通过应用一种新方法制备，即N-末端到精氨酸侧链环化。大多数肽作为 Y ₄ R 部分激动剂，与线性前体肽相比，显示出高达 60 倍的 Y _{4 R 亲和力。}两个环状六肽 ( 18 , 24 ) 显示出更高的 Y ₄R 效力（Ca ²⁺水母发光蛋白测定），并且在 p K _i值 >10 的情况下，与人胰多肽 (hPP) 相比，Y _{4 R 亲和力也更高。}化合物如18和24 ，与 PP 和先前描述的具有高 Y ₄ R 亲和力的二聚肽配体相比，表现出相当低的分子量和明显更显着的 Y ₄ R 选择性，代表了制备标记工具化合物的有希望的线索，并可能支持开发药物样Y ₄ R 配体。