SOM230: a new somatostatin peptidomimetic with potent inhibitory effects on the growth hormone/insulin-like growth factor-I axis in rats, primates, and dogs.
SOM230: a new somatostatin peptidomimetic with potent inhibitory effects on the growth hormone/insulin-like growth factor-I axis in rats, primates, and dogs.
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SOM230：一种新型生长抑素肽模拟物，对大鼠、灵长类动物和狗的生长激素/胰岛素样生长因子-I 轴具有有效的抑制作用。
DOI：
10.1210/en.2002-220219
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发表时间：
2002
期刊：
影响因子：
4.8
通讯作者：
C. Bruns
中科院分区：
文献类型：
--
作者：
G. Weckbecker;U. Briner;I. Lewis;C. Bruns
本项目的目标是寻找具有上级治疗潜力的生长抑素（SRIF）类似物。新的SRIF类似物的受体结合研究用于揭示与个体人SRIF受体亚型（sst 1-sst 5）相互作用的SRIF亚结构。将这些亚结构并入稳定的环己肽模板中产生了SOM 230，其以纳摩尔亲和力与sst 1、sst 2、sst 3和sst 5结合。在大鼠中，SOM 230对GH的抑制作用在注射后1小时与SMS 201-995（奥曲肽）相似，但在注射后6小时是其4倍，表明代谢稳定性增加。大鼠接受1和10 μ g/kg.h的SOM 230治疗后，第2天IGF-I血浆水平分别下降68%和90%（P < 0.01）;而接受SMS 201-995治疗后，血浆IGF-I水平分别下降28%和49%。大鼠输注2周后，SOM 230对IGF-I水平的抑制仍然明显，而对SMS 201-995的反应基本消失。SOM 230对IGF-I血浆水平的这种增强作用在8周研究中得到证实，其中两种类似物以50 μ g/kg/h输注大鼠。在恒河猴中，SOM 230和SMS 201-995处理导致GH抑制，半最大抑制剂量值分别为0.5和0.4 μ g/kg，但血浆IGF-I水平仅被SOM 230降低（-53%）。在食蟹猴中，2周输注SOM 230（但SMS 201-995的程度要小得多）显著降低血浆GH水平（从16.3 ng/ml降至1.8 ng/ml，P = 0.007）。在食蟹猴和比格犬中，输注SOM 230而非SMS 201-995均显著降低IGF-I水平。总之，SOM 230具有独特的结构，几乎普遍地与人ssts结合，并且有效地抑制GH/IGF-I轴跨物种。SOM 230是临床应用的候选药物。
The goal of this project was to find a somatostatin (SRIF) analog with superior therapeutic potential. Receptor binding studies of new SRIF analogs were used to reveal SRIF substructures that interact with individual human SRIF receptor subtypes (sst1-sst5). Incorporation of these substructures into a stable cyclohexapeptide template led to SOM230, which binds with nanomolar affinity to sst1, sst2, sst3, and sst5. In rats, the inhibitory effect of SOM230 on GH was similar to SMS 201-995 (octreotide) at 1 h, but was 4-fold more potent at 6 h post injection, indicating increased metabolic stability. Treatment of rats with SOM230, at 1 and 10 micro g/kg.h, decreased IGF-I plasma levels, on d 2, by 68% and 90% (P < 0.01); whereas, under SMS 201-995 treatment, plasma IGF-I levels decreased by 28% and 49%, respectively. After a 2-wk infusion of rats, the suppression of IGF-I levels by SOM230 was still pronounced, whereas the response to SMS 201-995 was largely lost. This enhanced effect of SOM230 on IGF-I plasma levels was confirmed in an 8-wk study where both analogs were infused at 50 micro g/kg/h in rats. In rhesus monkey, SOM230 and SMS 201-995 treatment resulted in GH inhibition, with half-maximal inhibitory dose values of 0.5 and 0.4 micro g/kg, respectively, but plasma IGF-I levels were only lowered by SOM230 (-53%). In cynomolgus monkeys, a 2-wk infusion of SOM230, but to a much lesser extent of SMS 201-995, lowered plasma GH levels significantly (from 16.3 to 1.8 ng/ml, P = 0.007). Both in cynomolgus monkeys and beagle dogs, infusion of SOM230, but not SMS 201-995, lowered IGF-I levels significantly. In conclusion, SOM230 has a unique structure, binds almost universally to human ssts, and inhibits potently the GH/IGF-I axis cross-species. SOM230 is a candidate drug for clinical use.
开发生长抑素受体亚型 sstr1 的选择性激动剂。
DOI：
--
发表时间：
1996
期刊：
The Journal of pharmacology and experimental therapeutics.
影响因子：
--
作者：
Liapakis,G;Hoeger,C;Rivier,J;Reisine,T
通讯作者：
Reisine,T
SST3 选择性有效肽生长抑素受体拮抗剂。
DOI：
10.1073/pnas.250483897
发表时间：
2000
影响因子：
11.1
作者：
Reubi,JC;Schaer,JC;Wenger,S;Hoeger,C;Erchegyi,J;Waser,B;Rivier,J
通讯作者：
Rivier,J
影响因子：
15.9
作者：
Shimon, I;Yan, XM;Melmed, S
通讯作者：
Melmed, S