Lanthionine-somatostatin analogs: synthesis, characterization, biological activity, and enzymatic stability studies.
Lanthionine-somatostatin analogs: synthesis, characterization, biological activity, and enzymatic stability studies.
复制标题
DOI：
--
复制
发表时间：
1997
影响因子：
7.3
通讯作者：
G. Osapay;L. Prokai;H. S. Kim;K. Medzihradszky;D. Coy;G. Liapakis;T. Reisine;G. Melacini;Q. Zhu;S. Wang;R. Mattern;M. Goodman
中科院分区：
文献类型：
--
作者：
G. Osapay;L. Prokai;H. S. Kim;K. Medzihradszky;D. Coy;G. Liapakis;T. Reisine;G. Melacini;Q. Zhu;S. Wang;R. Mattern;M. Goodman
一系列含有羊毛硫氨酸桥的环状生长抑素类似物已接受结构-活性关系的研究。通过在肟树脂 (PCOR) 上环化，然后在溶液中进行缩合反应，直接合成善宁的硫醚桥类似物 (1) (SMS 201,995) 和几种羊毛硫氨酸六肽、七肽和八肽。通过液体二次离子质谱 (LSIMS) 分析目标肽的结构，并在通过蛋白水解裂解打开肽环后进行高能碰撞诱导解离 (CID) 研究。通过测定这些化合物对大鼠垂体前叶细胞原代培养物中生长激素（GH）释放的抑制效力以及它们与克隆的生长抑素受体（SSTR1-5）的结合亲和力，评估了这些化合物的生物活性。通过引入羊毛硫氨酸桥对善宁进行结构修饰，显着提高了受体结合选择性。与生长抑素[1-14] 和善宁相比，C 端 Thr-ol (1) 的羊毛硫氨酸八肽对大鼠 SSTR5 表现出相似的高亲和力。然而，它对 mSSTR2b 的结合亲和力比善宁弱约 50 倍。类似地，C 端带有 Thr-NH2 残基的羊毛硫氨酸八肽 (2) 对 rSSTR5 的亲和力高于对 mSSTR2B 的亲和力。两种肽（化合物 1 和 2）抑制生长激素分泌的效力比善宁低得多。这与它们对 SSTR2 的亲和力一致，SSTR2 受体被认为与生长抑素及其类似物抑制生长激素释放有关。已在大鼠脑匀浆中研究了羊毛硫氨酸-善宁和善宁的代谢稳定性。尽管这两种化合物对酶降解都具有很高的稳定性，但羊毛硫氨酸类似物的半衰期比善宁长 2.4 倍。两种化合物的主要代谢物已通过体内技术（脑微透析）和质谱法进行分离和鉴定。
A series of cyclic somatostatin analogs containing a lanthionine bridge have been subjected to studies of structure-activity relationships. A direct synthesis of the thioether bridged analog (1) of sandostatin (SMS 201,995) and several lanthionine hexa-, hepta-, and octapeptides was carried out by using the method of cyclization on an oxime resin (PCOR) followed by condensation reactions in solution. The structures of the target peptides were analyzed by liquid secondary ion mass spectrometry (LSIMS) and subjected to high-energy collision-induced dissociation (CID) studies after opening of the peptide ring by proteolytic cleavage. The biological activities of these compounds have been evaluated by assaying their inhibitory potencies for the release of growth hormone (GH) from primary cultures of rat anterior pituitary cells, as well as by their binding affinities to cloned somatostatin receptors (SSTR1-5). The structural modification of sandostatin by introducing a lanthionine bridge resulted in a significantly increased receptor binding selectivity. The lanthionine octapeptide with C-terminal Thr-ol (1) showed similar high affinity for rat SSTR5 compared to somatostatin[1-14] and sandostatin. However, it exhibits about 50 times weaker binding affinity for mSSTR2b than sandostatin. Similarly, the lanthionine octapeptide with the C-terminal Thr-NH2 residue (2) has higher affinity for rSSTR5 than for mSSTR2B. Both peptides (compounds 1 and 2) have much lower potencies for inhibition of growth hormone secretion than sandostatin. This is consistent with their affinities to SSTR2, the receptor which is believed to be linked to the inhibition of growth hormone release by somatostatin and its analogs. The metabolic stability of lanthionine-sandostatin and sandostatin have been studied in rat brain homogenates. Although both compounds have a high stability toward enzymatic degradation, the lanthionine analog has a 2.4 times longer half-life than sandostatin. The main metabolites of both compounds have been isolated and identified by using an in vivo technique (cerebral microdialysis) and mass spectrometry.