SST3-selective potent peptidic somatostatin receptor antagonists.
SST3-selective potent peptidic somatostatin receptor antagonists.
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SST3 选择性有效肽生长抑素受体拮抗剂。
DOI：
10.1073/pnas.250483897
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发表时间：
2000
影响因子：
11.1
通讯作者：
Rivier,J
中科院分区：
文献类型：
--
作者：
Reubi,JC;Schaer,JC;Wenger,S;Hoeger,C;Erchegyi,J;Waser,B;Rivier,J
发现了一个通过二硫桥环化的生长抑素八肽衍生物家族（des-AA1,2,4,5,12,13[d-2Nal8]-somatostatin-14, ODN-8），它们对转染CCL39细胞的人sst3somatostatin受体亚型具有高亲和力和选择性。氨基甲酰-des- aa1,2,4,5,12,13[d-Cys3,Tyr7,d-Agl8（Me，2-萘酰基）]-生长抑素-14 （sst3-ODN-8）与生长抑素-28对sst3的结合亲和力相当，而与其他四种生长抑素受体亚型的结合亲和力不到千分之一。化合物sst3-ODN-8能有效逆转生长抑素28诱导的对福斯克林刺激的cAMP产生的抑制（pKB= 9.07），并逆转sst3转染CCL39细胞中生长抑素28诱导的磷脂酶C活性的刺激（pKi= 9.22）。[125I-Tyr7]sst3-ODN-8选择性标记表达sst3的细胞具有亚纳摩尔结合亲和力（KD= 0.27 nM）。使用这种放射配体，表达sst3的人类肿瘤，特别是无活性垂体腺瘤，可以通过受体放射自显影术识别；此外，人类淋巴网状系统表达sst3结合位点的区域被纳米摩尔浓度的sst3-ODN-8选择性地取代。基于3、7、8位取代类似物的构效关系，我们假设sst3选择性、高亲和力和可能拮抗的基础在于类似物的环大小和氨基甘氨酸8位n -甲基化氨基-2-萘基侧链的独特构象和结构特征，而不是tyr7取代或3位的构型。标记的和未标记的sst3-ODN-8类似物家族代表了高度创新、有效和特异性的sst3选择性拮抗剂工具，可用于研究sst3介导的生理和病理生理状况，可能提出新的临床应用。
A family of octapeptide derivatives of somatostatin cyclized via a disulfide bridge (des-AA1,2,4,5,12,13[d-2Nal8]-somatostatin-14, ODN-8) was identified that has high affinity and selectivity for the human sst3somatostatin receptor subtype transfected in CCL39 cells. The binding affinity of carbamoyl-des-AA1,2,4,5,12,13[d-Cys3,Tyr7,d-Agl8(Me,2-naphthoyl)]-somatostatin-14 (sst3-ODN-8) is equal to that of somatostatin-28 for sst3and less than one-thousandth that for the other four somatostatin receptor subtypes. Compound sst3-ODN-8 potently reverses the somatostatin-28-induced inhibition of forskolin-stimulated cAMP production (pKB= 9.07) and reverses the somatostatin-28-induced stimulation of phospholipase C activity (pKi= 9.22) in sst3-transfected CCL39 cells. [125I-Tyr7]sst3-ODN-8 selectively labels sst3-expressing cells with subnanomolar binding affinity (KD= 0.27 nM). With the use of this radioligand, sst3-expressing human tumors, particularly inactive pituitary adenomas, can be identified with receptor autoradiography; moreover, areas of the human lymphoreticular system express sst3binding sites selectively displaced by nanomolar concentrations of sst3-ODN-8. Based on the structure–activity relationship of selected analogs substituted at positions 3, 7, and 8, we hypothesize that the basis for sst3selectivity, high affinity, and possibly antagonism resides in the ring size of the analog and the unique conformational and structural character of the N-methylated amino-2-naphthoyl side chain of aminoglycine at position 8 and not in the Tyr7substitution or in thed-configuration at position 3. The family of labeled and unlabeled sst3-ODN-8 analogs represents highly innovative, potent, and specific sst3-selective antagonist tools for the study of sst3-mediated physiological and pathophysiological conditions that may suggest novel clinical applications.