Structure-activity relationships of somatostatin analogs in the rabbit ileum and the rat colon.
Structure-activity relationships of somatostatin analogs in the rabbit ileum and the rat colon.
复制标题
兔回肠和大鼠结肠中生长抑素类似物的结构-活性关系。
DOI：
10.1172/jci110838
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发表时间：
1983
期刊：
影响因子：
--
通讯作者：
Dharmsathaphorn,K
中科院分区：
文献类型：
--
作者：
Rosenthal,LE;Yamashiro,DJ;Rivier,J;Vale,W;Brown,M;Dharmsathaphorn,K
生长抑素增加内分泌肿瘤和短肠综合征患者电解质的吸收并抑制腹泻。在开发肠道特异性生长抑素类似物的尝试中，生长抑素分子中的每个氨基酸都被l -丙氨酸取代，删除或替换为其d -异构体。然后使用改进的乌辛室技术测定每种类似物刺激回肠离子转运的效力。将实验结果与各类似物抑制体外培养大鼠垂体前叶细胞促生长激素释放和抑制精氨酸促胰岛素和胰高血糖素释放的能力进行比较。显示出肠道选择性的类似物随后在大鼠结肠中测试了它们的离子传输特性。结果：(a)用l -丙氨酸替代或删除6,7,8或9号位置的氨基酸以及删除苏氨酸10产生的类似物，其离子传输特性显著降低，低于生长抑素作用的4%。这种替代还显著降低了化合物抑制生长激素、胰岛素和胰高血糖素释放的能力。(b)肠道离子转运的选择性是通过以下任何一种改变来实现的：l -丙氨酸取代苯丙氨酸11，删除苯丙氨酸11，在赖氨酸4上用d -赖氨酸取代，或在赖氨酸4上用l -丙氨酸取代。这些化合物的肠道离子转运特性分别为52%、34%、39%和94%，而对生长激素、胰岛素或胰高血糖素的释放几乎没有抑制。结论：(a)苯丙氨酸6、苯丙氨酸7、色氨酸8和赖氨酸9是生长抑素离子转运和其他生物作用所必需的，而苏氨酸10是必不可少的间隔剂。(b)改变苯丙氨酸11或赖氨酸4产生的类似物对离子在家兔回肠和大鼠结肠中的转运具有选择性。在开发肠道特异性生长抑素类似物以治疗腹泻时，应考虑到这些发现。
Somatostatin increases absorption of electrolytes and inhibits diarrhea in patients with endocrine tumors and short bowel syndrome. In an attempt to develop a gut-specific somatostatin analog, each amino acid in the somatostatin molecule was replaced with L-alanine, deleted, or substituted with its D-isomer. The potency of each analog to stimulate ion transport in the rabbit ileum was then determined using the modified Ussing chamber technique. The results were compared to the ability of each analog to inhibit the stimulated release of growth hormone from cultured rat anterior pituitary cells and to inhibit the arginine-stimulated release of insulin and glucagon in the rat in vivo. Analogs that showed gut selectivity were then tested for their ion transport properties in the rat colon. Results: (a) Substitution with L-alanine or deletion of the amino acid at position 6, 7, 8, or 9 and deletion of Threonine10-produced analogs with significantly reduced ion transport properties to <4% of somatostatin's action. The substitution also markedly reduced the ability of the compounds to inhibit the release of growth hormone, insulin, and glucagon. (b) Selectivity of intestinal ion transport was achieved by any one of the following alterations: L-alanine substitution at Phenylalanine11, deletion of Phenylalanine11, substitution with D-lysine at Lysine4, or substitution with L-alanine at Lysine4. These compounds had intestinal ion transport properties of 52, 34, 139, and 94%, respectively, while demonstrating little or no inhibition of growth hormone, insulin or glucagon release. Conclusions: (a) Phenylalanine6, Phenylalanine7, Tryptophan8, and Lysine9are required for the ion transport and other biologic actions of somatostatin, whereas Threonine10serves as an essential spacer. (b) Alteration at Phenylalanine11or Lysine4yields analogs that are selective for ion transport in the rabbit ileum and rat colon. These findings should be taken into consideration when developing a gut-specific somatostatin analog that can be useful in the treatment of diarrhea.