Effect of Low-Molecular-Weight Allosteric Agonists of the Luteinizing Hormone Receptor on Its Expression and Distribution in Rat Testes

Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats

“…This may be due to the more modest stimulatory effect of TP4/2 on the receptor, as illustrated by the magnitude of its stimulatory effects on progesterone production and steroidogenic gene expression compared to hCG, as well as the altered signaling bias triggered by this small molecule agonist. In this regard, it should be noted that upon long-term administration to male rats, TP4/2 and other thieno [2,3-d]-pyrimidine derivatives developed by us had a relatively weak effect on the expression of the Lhcgr gene in the testes, while hCG in this case significantly reduced it [24,28,49]. We and other authors have shown that allosteric agonists based on thieno [2,3-d]-pyrimidine structure are highly specific for G s proteins and cAMP-dependent signaling pathways, but have little effect on the activity of G q/11 proteins and phospholipase Cβ [15,23].…”

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…When TP03 was administered to metformin-treated diabetic rats, a significant increase in its steroidogenic effect was shown upon short-term (but not longterm) TP03 administration [402,406]. In contrast to hCG, long-term administration of TP03 and TP04 to male rats did not suppress the expression of the Lhr gene in the testes, and their steroidogenic effect was preserved and even increased, which indicates the possibility of their long-term use to stimulate testicular steroidogenesis in the conditions of androgen deficiency [400,401]. TP03 has been shown to stimulate ovarian steroidogenesis in proestrus adult female rats pretreated with a GnRH antagonist [408].…”

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…We have developed a series of thieno[2,3-d]-pyrimidine derivatives with the properties of allosteric agonists and (or) ago-PAMs and allosteric antagonists of LHR [ 324 , 325 , 394 , 395 , 396 , 397 , 398 , 399 , 400 , 401 , 402 ]. Compounds TP03 and TP04, the most active of the full agonists, stimulated the AC activity in testicular membranes isolated from the rat testes, increased testosterone production by the cultured Leydig cells, and also stimulated testicular steroidogenesis and increased testosterone levels when administered intraperitoneally, subcutaneously, and orally to both healthy male rats and animals with androgen deficiency caused by types 1 and 2 diabetes mellitus and aging [ 395 , 400 , 402 , 403 , 404 ].…”

“…When TP03 was administered to metformin-treated diabetic rats, a significant increase in its steroidogenic effect was shown upon short-term (but not long-term) TP03 administration [ 402 , 406 ]. In contrast to hCG, long-term administration of TP03 and TP04 to male rats did not suppress the expression of the Lhr gene in the testes, and their steroidogenic effect was preserved and even increased, which indicates the possibility of their long-term use to stimulate testicular steroidogenesis in the conditions of androgen deficiency [ 400 , 401 ]. The stimulating effect of TP03 on progesterone production and ovulation induction was shown by us in immature female rats pretreated with FSH [ 408 ], as well as in proestrus adult female rats pretreated with a GnRH antagonist [ 409 ].…”