The Study of Biological Activity of a New Thieno[2,3-D]-Pyrimidine-Based Neutral Antagonist of Thyrotropin Receptor

Derkach, K. V.; Fokina, Ekaterina; Bakhtyukov, A. A.; Sorokoumov, V. N.; Stepochkina, Anna; Захарова, И. О.; Шпаков, А. О.

doi:10.1007/s10517-022-05462-x

Cited by 7 publications

(3 citation statements)

References 14 publications

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

confidence: 99%

“…We have developed two thieno[2,3-d]-pyrimidine derivatives, TPY1 and TP48, with antagonistic activity against TSHR [ 350 , 351 ]. When administered to rats, TPY1 reduced thyroliberin-stimulated production of thyroid hormones and the expression of thyroglobulin, thyroperoxidase, and Na + /I − symporter genes in the thyroid but did not affect basal levels of thyroid hormones indicating its activity as a neutral allosteric TSHR antagonist [ 351 ]. In turn, TP48 not only suppressed thyroid hormones levels and expression of thyroid-specific genes stimulated by thyroliberin, but 3.5 h after administration to rats, it reduced the basal levels of thyroid hormones and the expression of the Nis gene encoding the Na + /I − symporter [ 350 , 351 ].…”

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

confidence: 99%

“…In turn, TP48 not only suppressed thyroid hormones levels and expression of thyroid-specific genes stimulated by thyroliberin, but 3.5 h after administration to rats, it reduced the basal levels of thyroid hormones and the expression of the Nis gene encoding the Na + /I − symporter [ 350 , 351 ]. This indicates that TP48 functions as a mild inverse TSHR agonist [ 351 ].…”

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

confidence: 99%

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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%

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

confidence: 99%

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

confidence: 99%

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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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Targeting Thyroid-Stimulating Hormone Receptor: A Perspective on Small-Molecule Modulators and Their Therapeutic Potential

Zhang,

Tan,

Zhang

et al. 2024

J. Med. Chem.

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TSHR is a member of the glycoprotein hormone receptors, a subfamily of class A G-protein-coupled receptors and plays pivotal roles in various physiological and pathological processes, particularly in thyroid growth and hormone production. The aberrant TSHR function has been implicated in several human diseases including Graves' disease and orbitopathy, nonautoimmune hyperthyroidism, hypothyroidism, cancer, neurological disorders, and osteoporosis. Consequently, TSHR is recognized as an attractive therapeutic target, and targeting TSHR with small-molecule modulators including agonists, antagonists, and inverse agonists offers great potential for drug discovery. In this perspective, we summarize the structures and biological functions of TSHR as well as the recent advances in the development of small-molecule TSHR modulators, highlighting their chemotypes, mode of actions, structure−activity relationships, characterizations, in vitro/in vivo activities, and therapeutic potential. The challenges, new opportunities, and future directions in this area are also discussed. ■ SIGNIFICANCE• Targeting TSHR represents a novel and promising therapeutic strategy in drug discovery. • The recent advances in small-molecule modulators of TSHR are systematically summarized, and the challenges and new opportunities as well as future directions in the field of TSHR-targeting drug discovery are discussed. • This perspective provides valuable insights for medicinal chemists to develop novel small molecules targeting TSHR in the future.

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Thyroid-Stimulating Hormone Receptor: the Role in the Development of Thyroid Pathology and Its Correction

Fokina

Шпаков²

2022

J Evol Biochem Phys

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One of the key elements responsible for the thyroid response to thyroid-stimulating hormone (TSH) is the TSH receptor (TSHR), which belongs to the G protein-coupled receptor superfamily. Binding of TSH or stimulatory autoantibodies to the TSHR extracellular domain triggers multiple signaling pathways in target cells that are mediated through various types of G proteins and β-arrestins. Inhibitory autoantibodies, in contrast, suppress TSHR activity, inducing hypothyroid states. Activating mutations lead to constitutively active TSHR forms and can trigger cancer. Therefore, the TSHR is one of the key targets for the regulation of thyroid function and thyroid status, as well as correction of diseases caused by changes in TSHR activity (autoimmune hyper- and hypothyroidism, Graves’ ophthalmopathy, thyroid cancer). TSH preparations are extremely rarely used in medicine due to their immunogenicity and severe side effects. Most promising is the development of low-molecular allosteric TSHR regulators with an activity of full and inverse agonists and neutral antagonists, which are able to penetrate into the allosteric site located in the TSHR transmembrane domain and specifically bind to it, thus controlling the ability of the receptor to interact with G proteins and β-arrestins. Allosteric regulators do not affect the binding of TSH and autoantibodies to the receptor, which enables mild and selective regulation of thyroid function, while avoiding critical changes in TSH and thyroid hormone levels. The present review addresses the current state of the problem of regulating TSHR activity, including the possibility of using ligands of its allosteric sites.

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The Study of Biological Activity of a New Thieno[2,3-D]-Pyrimidine-Based Neutral Antagonist of Thyrotropin Receptor

Cited by 7 publications

References 14 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

Targeting Thyroid-Stimulating Hormone Receptor: A Perspective on Small-Molecule Modulators and Their Therapeutic Potential

Thyroid-Stimulating Hormone Receptor: the Role in the Development of Thyroid Pathology and Its Correction

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