Iyengar S, Li D L, Simmons R M
Lilly Neuroscience, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA.
J Pharmacol Exp Ther. 1999 May;289(2):1031-40.
The stimulation of food consumption after i.c.v. administration of various neuropeptide Y (NPY) receptor agonists was examined in CD-1 mice. These agonists, including endogenous peptides NPY, peptide YY (PYY), and pancreatic polypeptide, as well as several N-terminal truncated and synthetic peptides that are prototypic receptor agonists at Y1-Y6 NPY receptors ([Leu31Pro34]NPY, NPY2-36, NPY3-36, NPY13-36, PYY3-36, Pro34PYY, and D-Trp32NPY), showed varying abilities to elicit food consumption such that PYY > NPY2-36 = NPY = PYY3-36 > Pro34PYY > NPY3-36 >> [Leu31Pro34]NPY > NPY13-36 = D-Trp32NPY = pancreatic polypeptide. Published reports have suggested that NPY-induced feeding is mediated via the Y1 or the Y5 receptor subtypes. However, the relative ability of the various peptide analogs to elicit feeding differed from the relative ability of these peptides to bind to cloned Y1-Y6 receptors. The effects of prototypic Y1 receptor antagonists on NPY-induced feeding were also evaluated after i.c.v. administration. GR231118 (1229U91), a peptide Y1 antagonist, did not block NPY-induced feeding at the doses tested. BIBP3226, a nonpeptide Y1 receptor antagonist, as well as its opposite enantiomer, BIBP3435, which is inactive at Y1 receptors, blocked feeding elicited by NPY, [Leu31Pro34], or PYY at doses that did not cause overt behavioral dysfunction. The lack of effects with GR231118 and the nonstereoselective effects of BIBP3226 suggested that NPY-induced feeding in mice was not mediated via the Y1 receptor. Thus, by using currently available prototypic peptide NPY receptor agonists for Y1-Y6 receptors and peptide and nonpeptide Y1 receptor antagonists GR231118 and BIBP3226, the mediation of NPY-induced feeding cannot be unequivocally attributed to any one of the known NPY receptors. It is possible that NPY-induced feeding is mediated either by a combination of more than one NPY receptor subtype or by a unique NPY receptor subtype. Additional subtype-selective receptor antagonists, when available, will help to clarify this issue further.
在CD-1小鼠中研究了脑室内注射各种神经肽Y（NPY）受体激动剂后对食物消耗的刺激作用。这些激动剂包括内源性肽NPY、肽YY（PYY）和胰多肽，以及几种N端截短的和合成的肽，它们是Y1 - Y6 NPY受体的原型受体激动剂（[Leu31Pro34]NPY、NPY2 - 36、NPY3 - 36、NPY13 - 36、PYY3 - 36、Pro34PYY和D-Trp32NPY），它们引发食物消耗的能力各不相同，即PYY > NPY2 - 36 = NPY = PYY3 - 36 > Pro34PYY > NPY3 - 36 >> [Leu31Pro34]NPY > NPY13 - 36 = D-Trp32NPY = 胰多肽。已发表的报告表明，NPY诱导的进食是通过Y1或Y5受体亚型介导的。然而，各种肽类似物引发进食的相对能力与这些肽与克隆的Y1 - Y6受体结合的相对能力不同。还评估了原型Y1受体拮抗剂对脑室内注射NPY诱导的进食的影响。肽Y1拮抗剂GR231118（1229U91）在测试剂量下未阻断NPY诱导的进食。非肽Y1受体拮抗剂BIBP3226及其对映体BIBP3435（在Y1受体上无活性）在不引起明显行为功能障碍的剂量下阻断了NPY、[Leu31Pro34]或PYY诱导的进食。GR231118无效以及BIBP3226的非立体选择性作用表明，小鼠中NPY诱导的进食不是通过Y1受体介导的。因此，通过使用目前可用的Y1 - Y6受体的原型肽NPY受体激动剂以及肽和非肽Y1受体拮抗剂GR231118和BIBP3226，NPY诱导的进食的介导作用不能明确归因于任何一种已知的NPY受体。有可能NPY诱导的进食是由一种以上NPY受体亚型的组合介导的，或者是由一种独特的NPY受体亚型介导的。如果有更多亚型选择性受体拮抗剂，将有助于进一步阐明这个问题。
