Y1 and Y2 receptor selective neuropeptide Y analogues: evidence for a Y1 receptor subclass.
Y1 and Y2 receptor selective neuropeptide Y analogues: evidence for a Y1 receptor subclass.
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Y1 和 Y2 受体选择性神经肽 Y 类似物：Y1 受体亚类的证据。
DOI：
10.1021/jm00022a024
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发表时间：
1995
影响因子：
7.3
通讯作者：
Rivier,JE
中科院分区：
文献类型：
--
作者：
Kirby,DA;Koerber,SC;May,JM;Hagaman,C;Cullen,MJ;Pelleymounter,MA;Rivier,JE
使用反馈的结构-活性关系，我们还描述了特定的取代和桥接安排的优化，导致其他截断的，高亲和力的Yi选择性类似物的结合，如NPY本身，在低纳摩尔范围内的生产。最有意义的是，当检测des-AA 10 - 17-cycZo-7'21 [Cys 7 '21，Pro 34] NPY（11）抑制SK-N-M人神经母细胞瘤细胞中去甲肾上腺素刺激的cAMP释放的能力时，发现其具有与天然NPY分子相当的激动剂性质。化合物11还引起麻醉大鼠的血压升高。然而，在两个中枢神经系统模型的Yi受体功能，刺激喂养和anxiolyticactivity，这种类似物是无活性的，这表明存在一个新的受体亚类。总之，本结果表明，NPY的残基10 - 17不直接参与Y1或Y2受体的识别或激活。这表明，NPY受体的选择性是高度依赖于微妙的构象变化，如取代残基34脯氨酸或引入分子内的限制。此外，我们已经产生了选择性激活外周NPY Yi受体的NPY类似物。
Using the feedback from structure-activity relationships, we also describe the optimization of specific substitutions and bridging arrangements leading to the productionof other truncated, high-affinity Yi selective analogues which bind, as does NPY itself, in the low-nanomolar range. Of greatestsignificance, des-AA10 “17-cycZo-7/21 [Cys7'21, Pro34] NPY (11) was found to possess agonistic properties with an affinity comparable to that of the native NPY molecule when tested for its ability to inhibit norepinephrine-stimulated cAMP release in SK-N-MChuman neuroblastoma cells. Compound 11 also caused an increase in blood pressure in anesthetized rats. However, in two central nervous system models of Yi receptor function, stimulation of feeding and anxiolyticactivity, this analogue was inactive, which suggests the presence of a new subclass of receptors. In summary, the presentresults demonstrate that residues 10-17 of NPY are not directly involved in either Yi or Y2 receptor recognition or activation. This suggests that the selectivity of NPY receptors is highly dependent on subtle conformational changes such as the substitution of residue 34 to a proline or the introduction of intramolecular constraints. Additionally, we have produced an analogue of NPY that selectively activates peripheral NPY Yi receptors.