Nonpeptide somatostatin agonists with sst4 selectivity:: Synthesis and structure-activity relationships of thioureas
Nonpeptide somatostatin agonists with sst4 selectivity:: Synthesis and structure-activity relationships of thioureas
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DOI：
10.1021/jm980118e
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发表时间：
1998-11-19
影响因子：
7.3
通讯作者：
Crider, AM
中科院分区：
文献类型：
--
作者：
Liu, SQ;Tang, C;Crider, AM
利用NNC 26-9100（11）作为结构先导，合成了多种生长抑素的非肽衍生物，并评价了sst（2）和sst（4）受体结合亲和力。利用一种新型硫脲支架连接（1）杂芳环模拟色氨酸（8）残基，（2）非杂芳环模拟苯丙氨酸（7），（3）伯胺或其他碱性基团模拟生长抑素的赖氨酸（9）残基。使用来自表达ssts的细胞系[BHK细胞（sst（4））和HEK 293细胞（sst（2））]的膜进行置换研究，使用[I-125]Tyr（11）-SRIF作为放射性配体。几种硫脲（11、38、39、41和42）和脲66表现出小于100 nM的Ki值。硫脲11（Ki = 6 nM）和41（Ki = 16 nM）以及脲66（Ki = 14 nM）被认为是已知的最有效的非肽类sst（4）激动剂。由于硫脲11和脲66具有很高的sst选择性，这些新的非肽衍生物可能是研究sst（4）受体的有用工具。目前正在进行研究，以评价NNC 26-9100（11）治疗青光眼的治疗潜力。
Utilizing NNC 26-9100 (11) as a structural lead, a variety of nonpeptide derivatives of somatostatin were synthesized and evaluated for sst(2) and sst(4) receptor binding affinity. A novel thiourea scaffold was utilized to attach (1) a heteroaromatic nucleus to mimic the Trp(8) residue, (2) a nonheteroaromatic nucleus to mimic Phe(7), and (3) a primary amine or other basic group to mimic the Lys(9) residue of somatostatin. Displacement studies were carried out using membranes from cell lines expressing ssts [BHK cells (sst(4)) and HEK 293 cells (sst(2))] utilizing [I-125]Tyr(11)-SRIF as the radioligand. Several thioureas (11, 38, 39, 41, and 42) and the urea 66 exhibited K-i values of less than 100 nM. The thioureas 11 (K-i = 6 nM) and 41 (K-i = 16 nM) and the urea 66 (K-i = 14 nM) are believed to be the most potent nonpeptide sst(4) agonists known. Since the thiourea 11 and the urea 66 exhibit high ssts selectivity, these novel nonpeptide derivatives may be useful tools for studying the sst(4) receptor. Studies are currently in progress to evaluate the therapeutic potential of NNC 26-9100 (11) in the treatment of glaucoma.