Structure-activity studies on position 14 of human alpha-calcitonin gene-related peptide.
Structure-activity studies on position 14 of human alpha-calcitonin gene-related peptide.
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人α-降钙素基因相关肽14位的结构活性研究。
DOI：
10.1021/jm9608164
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Smith,DD
中科院分区：
文献类型：
--
作者：
Li,J;Matsuura,JE;Waugh,DJ;Adrian,TE;Abel,PW;Manning,MC;Smith,DD
用结构−活性研究探讨了人降钙素基因相关肽(h-α-α)第14位在激活降钙素基因相关肽受体中的作用。有趣的是，h-α-cGRP的第14位含有一个甘氨酰残基，是跨越8个α残基的−-螺旋的一部分。[Ala14]-h-α-cGRP、[AIb14]-h-α-cgrp、[asp14]-h-α-cgrp、[Asn14]-h-α-cgrp和[pro14]-h-α-cgrp是用固相多肽方法合成的。用圆二色谱测定了其二级结构。激动剂活性测定为类似物刺激豚鼠胰腺腺泡分泌淀粉酶和松弛预先收缩的猪冠状动脉的能力。类似物[Ala14]-h-α-cgrp、[Aib14]-h-α-cgrp、[asp14]-h-α-cgrp和[Asn14]-h-α-cgrp在两个组织中均含有高螺旋倾向的残基，与h-α-cgrp相比，在两种组织中都是有效的完全激动剂。有趣的是，用这些残基取代h-α-CGRP的Gly14并没有显著增加这些类似物的螺旋含量。[Pro14]-h-α-CGRP的螺旋含量明显降低，是一种效力较弱的冠状动脉激动剂，已知含有降钙素基因相关肽-1受体亚型，是胰腺腺泡细胞的拮抗剂，已知含有降钙素基因相关肽-2受体亚型。综上所述，14位残基在稳定横跨8个α-18残基的−-螺旋结构中起着重要作用。α-螺旋对于维持h-α-CGRP在其受体上高效的激动剂作用是至关重要的。在不对激动剂作用进行实质性修饰的情况下，在第14位可以耐受的各种官能团表明，该位置的残基不与CGRP受体接触。[Pro14]-h-α-cGRP可能是区分cGRP-1和cGRP-2受体亚型的一种有用的药理学工具。
A structure−activity study was performed to examine the role of position 14 of human α-calcitonin gene-related peptide (h-α-CGRP) in activating the CGRP receptor. Interestingly, position 14 of h-α-CGRP contains a glycyl residue and is part of an α-helix spanning residues 8−18. Analogues [Ala14]-h-α-CGRP, [Aib14]-h-α-CGRP, [Asp14]-h-α-CGRP, [Asn14]-h-α-CGRP, and [Pro14]-h-α-CGRP were synthesized by solid phase peptide methodology and purified by RP-HPLC. Secondary structure was measured by circular dichroism spectroscopy. Agonist activities were determined as the analogues' ability to stimulate amylase secretion from guinea pig pancreatic acini and to relax precontracted porcine coronary arteries. Analogues [Ala14]-h-α-CGRP, [Aib14]-h-α-CGRP, [Asp14]-h-α-CGRP, and [Asn14]-h-α-CGRP, all containing residues with a high helical propensity in position 14, were potent full agonists compared to h-α-CGRP in both tissues. Interestingly, replacement of Gly14of h-α-CGRP with these residues did not substantially increase the helical content of these analogues. [Pro14]-h-α-CGRP, predictably, has significantly lower helical content and is a 20-fold less potent agonist on coronary artery, known to contain CGRP-1 receptor subtypes, and an antagonist on pancreatic acini, known to contain CGRP-2 receptor subtypes. In conclusion, the residue in position 14 plays a structural role in stabilizing the α-helix spanning residues 8−18. The α-helix is crucial for maintaining highly potent agonist effects of h-α-CGRP at CGRP receptors. The wide variety of functional groups that can be tolerated in position 14 with no substantial modification of agonist effects suggests the residue in this position is not in contact with the CGRP receptor. [Pro14]-h-α-CGRP may be a useful pharmacological tool to distinguish between CGRP-1 and CGRP-2 receptor subtypes.