A characteristic feature of type 1 diabetes mellitus (DM1) in humans and experimental animals is an androgen deficiency, which is usually compensated by using the gonadotropin preparations with the activity of the agonists of the luteinizing hormone (LH) receptor, including human chorionic gonadotropin (hCG). However, the use of gonadotropins is associated with a number of undesirable effects, and their steroidogenic effect is weakened at the conditions of DM1. An alternative to gonadotropins can be low molecular weight thienopyrimidine-based agonists of the LH/hCG receptor, which bind to an allosteric site located within the transmembrane channel of this receptor. In this study the stimulating effect of hCG and the thienopyrimidine derivative TP03 we have developed earlier on the adenylyl cyclase (AC) in the testicular membranes of male rats with moderate/severe streptozotocin DM1 have been investigated along with the effects of hCG and TP03 on the plasma testosterone levels and the gene expression of steroidogenic proteins in the testes of diabetic rats under a single or 5-day administration of these drugs. In DM1, the AC-stimulating effects of hCG, TP03, and guanine nucleotides were decreased in the testicular membranes, and the EC50 of the effects of hCG and TP03 were increased; this indicated a reduced sensitivity of the LH/hCG receptors to hCG and TP03 in DM1 and could be associated with a decrease in functional activity of heterotrimeric G proteins. In diabetic rats with reduced basal testosterone levels, the steroidogenic effects of the single-dose hCG and TP03 were significantly reduced; and the effect of hCG was significantly higher than that of TP03. In the case of a 5-day treatment of diabetic rats with hCG and TP03, only the steroidogenic effect of gonadotropin was reduced, while the corresponding effect of TP03 did not change and was comparable to the effect of hCG. The regulatory effects of TP03 on the expression of steroidogenic proteins in the testes of control and diabetic rats were similar under the 5-day administration. The TP03 compound, in contrast to hCG, in the control and diabetic groups, did not reduce the expression of the Lhr gene, which encodes LH/hCG receptor, thereby preventing a decrease in the sensitivity of the testes to gonadotropins in DM1. Thus, a low molecular weight agonist TP03 is an effective stimulator of testosterone synthesis in severe DM1 with androgen deficiency.

中文翻译：

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促黄体激素受体的低分子量激动剂刺激 1 型糖尿病大鼠睾丸膜中的腺苷酸环化酶和睾丸中的类固醇生成

人类和实验动物 1 型糖尿病 (DM1) 的一个特征是雄激素缺乏，这通常通过使用具有促黄体生成素 (LH) 受体激动剂（包括人绒毛膜促性腺激素）活性的促性腺激素制剂来补偿。 hCG）。然而，促性腺激素的使用与许多不良作用有关，并且它们的类固醇生成作用在 DM1 条件下减弱。促性腺激素的替代物可以是基于低分子量噻吩并嘧啶的 LH/hCG 受体激动剂，它与位于该受体跨膜通道内的变构位点结合。在这项研究中，我们研究了 hCG 和我们之前开发的噻吩并嘧啶衍生物 TP03 对中度/重度链脲佐菌素 DM1 雄性大鼠睾丸膜中腺苷酸环化酶 (AC) 的刺激作用，以及 hCG 和 TP03 对睾丸激素的影响。在单次或 5 天给药这些药物的情况下，糖尿病大鼠的睾丸中血浆睾酮水平和类固醇蛋白的基因表达。在DM1中，睾丸膜中hCG、TP03和鸟嘌呤核苷酸的AC刺激作用减弱，而hCG和TP03作用的EC50升高；这表明 LH/hCG 受体对 DM1 中 hCG 和 TPO3 的敏感性降低，并且可能与异源三聚体 G 蛋白的功能活性降低有关。在基础睾酮水平降低的糖尿病大鼠中，单剂量 hCG 和 TPO3 的类固醇生成作用显着降低；hCG的作用显着高于TP03。在用hCG和TP03治疗糖尿病大鼠5天的情况下，只有促性腺激素的类固醇生成作用降低，而TP03的相应作用没有变化，与hCG的作用相当。5天给药后，TP03对对照组和糖尿病大鼠睾丸中类固醇蛋白表达的调节作用相似。与 hCG 相比，在对照组和糖尿病组中，TP03 化合物不会降低 Lhr 基因的表达，该基因编码 LH/hCG 受体，从而防止睾丸对 DM1 中促性腺激素的敏感性降低。因此，