Synthesis and hypertensive activity of neuropeptide Y fragments and analogues with modified N- or C-termini or D-substitutions.
Synthesis and hypertensive activity of neuropeptide Y fragments and analogues with modified N- or C-termini or D-substitutions.
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具有修饰的 N-或 C-末端或 D-取代的神经肽 Y 片段和类似物的合成和高血压活性。
DOI：
10.1021/jm00123a014
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发表时间：
1989
影响因子：
7.3
通讯作者：
Rivier,JE
中科院分区：
文献类型：
--
作者：
Boublik,JH;Scott,NA;Brown,MR;Rivier,JE
合成了猪神经肽Y （NPY）、NPY片段以及D-Xaa”、Ala9、D-Ala9和Met17在c端或n端取代或修饰的类似物。这些肽的合成和纯化是通过常规的实验室策略和技术实现的。在动脉内给药15分钟后，监测这些肽改变有意识大鼠平均动脉压（MAP）和心率（HR）的能力。这些肽相对于NPY的效价和疗效是通过比较剂量-反应曲线来确定的。给药40 Mg/kg NPY导致平均动脉压从107.0±2.6 mmHg的基础值迅速上升到157±5.5 mmHg（平均值±sem，= 13）。该反应的EDM（±SE）为3.04±0.88 Mg/kg。猪胰多肽（pPP）在40 Mg/kg时无活性（= 4），但其ED50（±SE,= 3）为0.76±0.24 Mg/kg。[Ac-Tyr^ NPY,[Ac-D-TyPjNPY，[des-氨基- tyr1] NPY和[Me-Tyr1] NPY的相对效价范围为1.1到2.2。2-6位和8-13位的d取代相对于NPY的势为0.1 ~ 1.0。d -取代位置1-3的类似物表现出延长的作用时间。含33-35位d取代的类似物在40 Mg/kg时无活性，而[D-Tyr^ NPY的效力比NPY低10倍，这表明c端区域的完整性对NPY的整体生物学作用至关重要。这一结论得到了对c端和n端缺失肽的研究的支持。2-3ß在40 Mg/kg时表现出充分的内在活性，并保持NPY 40%的降压效力。n端进一步缺失后，疗效依次下降。与NPY2-36的结果相反，将c端由天然羧酸修饰为游离羧酸或通过删除c端残基可以得到在40 Mg/kg时无活性的类似物。这些数据表明，在动脉内给药NPY和NPY类似物后，在有意识的大鼠中观察到高血压活动需要一个全长的、c端修饰的NPY结构。
Porcine neuropeptide Y (NPY), NPY fragments, and analogues with D-Xaa", Ala9, D-Ala9, and Met17 substitutions or modifications to the C-or N-termini were synthesized. The synthesis and purification of these peptides was achieved by using routine laboratory strategies and techniques. The ability of these peptides to alter mean arterial pressure (MAP) and heart rate (HR) in conscious rats was monitored for 15 min following intraarterial administration. Potencies and efficacies of these peptides relative to NPY were determined by comparison of dose-response curves. Administration of 40 Mg/kg NPY resulted in a rapid, though short-lived, rise in mean arterial pressure from a basal value of 107.0±2.6 to 157±5.5 mmHg (means±sem,= 13). The EDM (±SE) for this response was 3.04±0.88 Mg/kg. Peptide YY (PYY) elicited a response that was similar in magnitude but with an ED50 (±SE,= 3) of 0.76±0.24 Mg/kg while porcine pancreatic polypeptide (pPP) was inactive when tested at 40 Mg/kg (= 4). Relative potencies for [Ac-Tyr^ NPY,[Ac-D-TyPjNPY,[des-amino-Tyr1] NPY, and [Me-Tyr1] NPY ranged from 1.1 to 2.2. Potencies relative to NPY for D-substitutions at positions 2-6and 8-13 inclusive ranged from 0.1 to 1.0. Analogues with D-substitutionsat positions 1-3 exhibited an extended duration of action. Analogues with D-substitutionsat positions 33-35 inclusive were inactive at 40 Mg/kg, and [D-Tyr^ NPY was 10-fold less potent than NPY, suggesting that the integrityof the C-terminal region is critical to the overall biological actionof NPY. This conclusion is supported by studies with C-and N-terminal deletionpeptides. 2-3ß showed full intrinsic activity at 40 Mg/kg andretains 40% of the hypertensive potency of NPY. There was a sequential decrease in efficacy upon further N-terminal deletion. In contrast to the finding with NPY2-36, modification of the C-terminus either from the native carboxamide to the free carboxylic acid or by deletion of the C-terminal residue resulted in analogues which were inactive at 40 Mg/kg. Thesedata indicate that an essentially full-length, C-terminally amidated NPY structure is required for thehypertensive activity observed in conscious rats upon intraarterial administration of NPY and NPY analogues.