Peptide analogue studies of the hypothalamic neuropeptide Y receptor mediating pituitary adrenocorticotrophic hormone release

Hypothalamic neuropeptide Y (NPY) is thought to be important in the regulation of feeding and also in the release of Adrenocorticotrophic hormone (ACTH). Intracerebroventricular administration of NPY to male rats significantly increased plasma ACTH 10 min after injection and stimulated 2-h food intake. A series of analogues of NPY that have a greatly reduced affinity for the Y1 [human pancreatic polypeptide (human PP), NPY(3–36)], the Y2 ([Pro(34)]NPY, human PP), the Y3 (peptide YY), and the Y6 (human PP) receptor, all markedly stimulated ACTH release. Rat PP, which binds with high affinity to the Y4 receptor, was unable to stimulate ACTH release. A novel analogue fragment [Pro(34)]NPY(13–36) was synthesized as a ligand with low Y1 and Y2 receptor affinity. Interestingly, neither [Pro(34)]NPY(13–36) nor the selective Y5 receptor agonist [d-Trp(32)]NPY stimulated food intake, whereas both significantly increased plasma ACTH. Thus the hypothalamic NPY receptor mediating increases in plasma ACTH has a fragment activation profile unlike the Y1–Y4 or Y6 receptors and appears distinct from the NPY receptor controlling food intake.

下丘脑神经肽Y（Hypothalamic neuropeptide Y, NPY）被认为在摄食调控以及促肾上腺皮质激素（Adrenocorticotrophic hormone, ACTH）的释放过程中具有重要作用。向雄性大鼠侧脑室给予NPY后，给药10分钟时血浆ACTH水平显著升高，同时可刺激2小时的摄食量。一系列对Y1受体（配体包括人胰多肽（human pancreatic polypeptide, human PP）与NPY(3–36)）、Y2受体（配体包括[Pro(34)]NPY与human PP）、Y3受体（配体为肽YY（peptide YY））以及Y6受体（配体为human PP）的亲和力大幅降低的NPY类似物，均能显著促进ACTH释放。而对Y4受体具有高结合亲和力的大鼠胰多肽（Rat PP）则无法刺激ACTH释放。研究人员合成了一种新型类似物片段[Pro(34)]NPY(13–36)，该配体对Y1和Y2受体的亲和力较低。值得注意的是，[Pro(34)]NPY(13–36)与选择性Y5受体激动剂[d-Trp(32)]NPY均未促进摄食，但二者均可显著升高血浆ACTH水平。因此，介导血浆ACTH升高的下丘脑NPY受体，其片段激活谱与Y1-Y4或Y6受体均存在差异，且明显区别于调控摄食的NPY受体。