Structure-activity studies on the N-terminal region of growth hormone releasing factor.
Structure-activity studies on the N-terminal region of growth hormone releasing factor.
复制标题
生长激素释放因子N-末端区域的结构-活性研究。
DOI：
10.1021/jm00380a006
复制
发表时间：
1985
影响因子：
7.3
通讯作者：
Lance,VA
中科院分区：
文献类型：
--
作者：
Coy,DH;Murphy,WA;Sueiras-Diaz,J;Coy,EJ;Lance,VA
在以前的报道中，我们证明了人胰腺生长激素释放因子N-末端区域的构象限制的影响，在位置1，2或3的D-氨基酸取代导致在体内和体外生长激素释放活性大大增加。在戊巴比妥钠麻醉的大鼠中，最具活性的化合物[D-Ala-2] GRF（1-29）NH 2的活性是母体29个氨基酸肽的51倍。这些观察结果现在已经扩展到在这三个位置含有多个D-氨基酸取代的类似物。再次，超激动剂效力范围从1200%至3800%的肽，获得固相合成和纯化后，通过中压反相液相色谱。[D-Asn-8]-和[d-Ala-4] GRF（1-29）NH_2的活性分别是GRF（1 - 29）NH_2的2.43倍和1.1倍。相比之下，[D-Phe-6]和[D-Thr-7]类似物几乎没有活性。Chou-Fasman结构预测表明，肽的前三个残基假定没有固定的构象类型，但在残基6和10之间可能存在反转。试图用这些计算来合理化生物学结果。还研究了其他侧链对2位D-氨基酸的影响。Ac-[D-Phe-2]-和Ac-[D-Arg-2]肽的活性都很低。几种无活性的肽作为GRF的可能拮抗剂进行了测试;然而，在联合给药后，没有一种能够阻断GRF（1-29）NH 2的刺激作用。
In previous reports illustrating the effects of conformational restriction of the N-terminal region of human pancreatic growth hormone releasing factor, we demonstrated that D-amino acid substitutionsin either of positions 1, 2, or 3 resulted in greatly increased growth hormone releasing activity both in vivo and in vitro. The most active compound,[D-Ala-2] GRF (1-29) NH2, was 51 times more active than the parent 29 amino acid peptide in the sodium pentobarbital anesthetized rat. These observations have now been extendedto analogues containing multiple D-amino acid replacements in these three positions. Once again, peptides with superagonist potencies ranging from 1200% to 3800% were obtained after solid-phase synthesis and purification by medium-pressure reverse-phase liquid chromatography. In addition, it was found that [D-Asn-8]-and [d-Ala-4] GRF (1-29) NH¡¡ were, respectively, 2.43 and 1.1 times more active than GRF (1-29) NH2 itself. In contrast,[D-Phe-6] and [D-Thr-7] analogues were virtually inactive. Chou-Fasman structural predictions suggest that the first three residues of the peptide assume no fixed type of conformationbut that a reverse turn could be present between residues 6 and 10. Attempts are made to rationalize the biological results with these calculations. The effects of other side chains on the D-amino acid in position 2 were also investigated. Both the Ac-[D-Phe-2]-and Ac-[D-Arg-2] peptides had very low activity. Several of the inactive peptides were tested as possible antagonists of GRF; however, none was able to block the stimulatory effects of GRF (1-29) NH2 after combined administration.