The Effect of Low-Molecular-Weight Allosteric Agonist of Luteinizing Hormone Receptor on Functional State of the Testes in Aging and Diabetic Rats

Derkach, K. V.; Bakhtyukov, A. A.; Morina, I. Yu.; Dar’in, Dmitry; Sorokoumov, V. N.; Шпаков, А. О.

doi:10.1007/s10517-021-05177-5

Cited by 7 publications

(2 citation statements)

References 15 publications

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“…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 ]. Using molecular docking, it was found that the efficiency and selectivity of the studied thieno[2,3-d]-pyrimidines correlate with the characteristics of their binding to the transmembrane allosteric site of LHR, and the key parameter of such binding was the intensity of hydrophobic contact while the Coulomb interactions and hydrogen bonds were less significant [ 400 ].…”

Section: Allosteric Regulators Of Pituitary Glycoprotein Hormone Rece...mentioning

confidence: 99%

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

2023

IJMS

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Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators of GPCRs are simple ions, various biomolecules, and protein components of GPCR signaling (G proteins and β-arrestins). The stability and functional activity of GPCR complexes is also due to multicenter allosteric interactions between protomers. The complexity of allosteric effects caused by numerous regulators differing in structure, availability, and mechanisms of action predetermines the multiplicity and different topology of allosteric sites in GPCRs. These sites can be localized in extracellular loops; inside the transmembrane tunnel and in its upper and lower vestibules; in cytoplasmic loops; and on the outer, membrane-contacting surface of the transmembrane domain. They are involved in the regulation of basal and orthosteric agonist-stimulated receptor activity, biased agonism, GPCR-complex formation, and endocytosis. They are targets for a large number of synthetic allosteric regulators and modulators, including those constructed using molecular docking. The review is devoted to the principles and mechanisms of GPCRs allosteric regulation, the multiplicity of allosteric sites and their topology, and the endogenous and synthetic allosteric regulators, including autoantibodies and pepducins. The allosteric regulation of chemokine receptors, proteinase-activated receptors, thyroid-stimulating and luteinizing hormone receptors, and beta-adrenergic receptors are described in more detail.

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Section: Allosteric Regulators Of Pituitary Glycoprotein Hormone Rece...mentioning

confidence: 99%

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

2023

IJMS

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“…Nevertheless, some thiazolidine analogs may exhibit biased signaling and mobilize either Gα s , Gα i or both. Similarly, recent in vivo studies have identified TP22 21 and Org43553 22 both of which are thieno[2,3-d]pyrimidine compounds as effective allosteric agonists of LHRs but might potentially influence different signal cascades downstream.…”

Section: Introductionmentioning

confidence: 99%

Receptor cavity-based screening reveals potential allosteric modulators of gonadotropin receptors in carp (Cyprinus carpio)

Atre,

Hollander-Cohen,

Lankry

et al. 2023

Preprint

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The gonadotropins follicle stimulating hormone (FSH) and luteinizing hormone (LH) are key regulators of sexual development and the reproductive cycle in vertebrates. Unlike most G protein-coupled receptors (GPCR), the FSHR and LHR have large extracellular domains containing multiple leucine-rich repeats, which leads to an elaborate mechanism of receptor activation via orthosteric sites that is difficult to manipulate synthetically. To bypass the orthosteric mechanism, in this study using carp as a model organism we identified allosteric sites capable of receptor activation on the transmembrane domain, which are spatially separated from the orthosteric sites. We have further generated pharmacophore hypothesis based on the structural motifs and exposed residues of these cavities. Using available online small compound libraries consisting of >70000 small molecules, we have thereon used receptor cavity-based hypothesis and other screening stages to identify potential modulators of the allosteric binding site on the carp FSHR and LHRin-silico. We then examined byin vitrotransactivation assay the effect of four candidate compounds on FSHR and LHR, as compared to the activity of native ligands. Our results reveal both specific and dual effective allosteric modulators for FSHR and LHR, demonstrating the potential of our approach for efficient pharmacophore-based screening.

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Comparative Study of the Restoring Effect of Metformin, Gonadotropin, and Allosteric Agonist of Luteinizing Hormone Receptor on Spermatogenesis in Male Rats with Streptozotocin-Induced Type 2 Diabetes Mellitus

et al. 2022

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The Effect of Low-Molecular-Weight Allosteric Agonist of Luteinizing Hormone Receptor on Functional State of the Testes in Aging and Diabetic Rats

Cited by 7 publications

References 15 publications

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

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

Receptor cavity-based screening reveals potential allosteric modulators of gonadotropin receptors in carp (Cyprinus carpio)

Comparative Study of the Restoring Effect of Metformin, Gonadotropin, and Allosteric Agonist of Luteinizing Hormone Receptor on Spermatogenesis in Male Rats with Streptozotocin-Induced Type 2 Diabetes Mellitus

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