Derkach K V, Legkodukh A S, Dar’in D V, Shpakov A O
Tsitologiia. 2016;58(8):602-9.
The regulation of the functional activity of luteinizing hormone (LH) receptor can be carried out by using gonadotropins or low-molecular weight agonists of this receptor, which, unlike gonadotropins, bind to an allosteric site located in the transmembrane channel of the receptor. Thienopyrimidine derivatives, the analogs of the compound Org 43553, the greatest interest among the low-molecular weight agonists. The aim of the work was synthesis of the novel thienopyrimidine derivatives, such as 5-amino-N-(tert-butyl)-4-(3-(2-methoxynicotinamido) phenyl)-2-(methylthio)thieno [2,3-d]pyrimidine-6-carboxamide (TP-21), 4-(3-(5-amino-6-(tert-butylcarbamoyl)- 2-) methylthio)thieno[2,3-d] pyrimidine-4-yl)phenyl)carbamoyl)pyridine 1-ocide (TP-22) and 5-amino-N-(tert-butyl)-4-(3-(2-chloronicotinamido)-2-(methylthio)thieno[2,3-d] pyrimidine-6-carboxamide (TP-23), and the study of their effects in vitro on adenylyl cyclase (AC) activity in testicular membranes of rats as well in vivo on the testosterone level in the case of their intratesticular and intraperitoneally administration into male rats. The compounds TP-21, TP-22 and TP-23 stimulated the basal AS activity in rat testicular membranes with the EC50 values, such as 1556, 358 and 372 nM, and ranked according to their efficiency in the following order: TP-23 > TP-21 TP-22. In the case of combined action of thienopyrimidines (10–4 M) and human chorionic gonadotropin (hCG, 10–8 M), the AC stimulating effect of gonadotropin was preserved, but at a concentration of 10–4 M, the additivity of AC effects of thienopyrimidines and hCG was observed. The TP-21, TP-22 and TP-23, when i. t. administered into male rats at a dose of 10 mg/kg, increased the testosterone levels, and, 5 h after treatment, the increase of concentration of testosterone over its value in the control group was 32.8, 36.4 and 76.9 nM respectively. When administered intraparenterally, TP-21 and TP-22 had a little effect on the testosterone level, while the compound TP-23 showed significant increase in the testosterone level at 1 and 3 h (the increase over control amounted 34.8 and 18.9 nM). The data obtained indicate a high activity of TP-23, as a stimulator of the synthesis and secretion of testosterone, as well as the prospect of development on its basis of highly effective agonists of LH receptor.
促黄体生成素（LH）受体功能活性的调节可通过使用促性腺激素或该受体的低分子量激动剂来实现，与促性腺激素不同的是，这些低分子量激动剂与位于受体跨膜通道中的变构位点结合。噻吩并嘧啶衍生物是化合物Org 43553的类似物，在低分子量激动剂中最受关注。这项工作的目的是合成新型噻吩并嘧啶衍生物，如5-氨基-N-（叔丁基）-4-（3-（2-甲氧基烟酰胺基）苯基）-2-（甲硫基）噻吩并[2,3-d]嘧啶-6-甲酰胺（TP-21）、4-（3-（5-氨基-6-（叔丁基氨基甲酰基）-2-（甲硫基）噻吩并[2,3-d]嘧啶-4-基）苯基）甲酰基）吡啶1-氧化物（TP-22）和5-氨基-N-（叔丁基）-4-（3-（2-氯烟酰胺基）-2-（甲硫基）噻吩并[2,3-d]嘧啶-6-甲酰胺（TP-23），并研究它们在体外对大鼠睾丸膜中腺苷酸环化酶（AC）活性的影响，以及在体内将它们经睾丸内和腹腔内注射给雄性大鼠后对睾酮水平的影响。化合物TP-21、TP-22和TP-23刺激大鼠睾丸膜中的基础AC活性，其EC50值分别为1556、358和372 nM，按其效率排序如下：TP-23＞TP-21＞TP-22。在噻吩并嘧啶（10–4 M）与人绒毛膜促性腺激素（hCG，10–8 M）联合作用的情况下，促性腺激素的AC刺激作用得以保留，但在10–4 M的浓度下，观察到噻吩并嘧啶和hCG的AC效应具有加和性。当以10 mg/kg的剂量经睾丸内给雄性大鼠注射TP-21、TP-22和TP-23时，睾酮水平升高，治疗5小时后，睾酮浓度相对于对照组的增加值分别为32.8、36.4和76.9 nM。当经肠胃外给药时，TP-21和TP-22对睾酮水平影响较小，而化合物TP-23在1小时和3小时时睾酮水平显著升高（相对于对照组的增加值分别为34.8和18.9 nM）。所获得的数据表明TP-23作为睾酮合成和分泌的刺激剂具有高活性，以及在此基础上开发LH受体高效激动剂的前景。
