Thyrotropin receptor antagonists and inverse agonists, and their potential application to thyroid diseases

Abstract

The thyrotropin receptor (TSHR) plays critical roles in thyroid growth and function and in the pathogenesis of several thyroid diseases including Graves' hyperthyroidism and ophthalmopathy, non-autoimmune hyperthyroidism and thyroid cancer. Several low-molecular weight compounds (LMWCs) and anti-TSHR monoclonal antibodies (mAbs) with receptor antagonistic and inverse agonistic activities have been reported. The former binds to the pocket formed by the receptor transmembrane bundle, and the latter to the extracellular TSH binding site. Both are effective inhibitors of TSH/ thyroid stimulating antibody-stimulated cAMP and/or hyaluronic acid production in TSHR-expressing cells. Anti-insulin-like growth factor 1 inhibitors are also found to inhibit TSHR signaling. Each agent has advantages and disadvantages; for example, mAbs have a higher affinity and longer half-life but are more costly than LMWCs. At present, mAbs appear most promising, yet the development of more efficacious LMWCs is desirable. These agents are anticipated to be efficacious not only for the above-mentioned diseases but also for resistance to thyroid hormone and have utility for thyroid cancer radionuclide scintigraphy/therapy as a new theranostic.

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

“…At the same time, these sites are targets for synthetic low-molecular-weight compounds, which, through allosteric mechanisms, can regulate the intrinsic and hormone-stimulated activity of TSHR ( Figure 4 ). At present, significant progress has been made both in the study of the configuration of TSHR transmembrane allosteric sites and in the development of small compounds that can bind to them and demonstrate the activity of allosteric regulators [ 317 , 318 , 319 , 320 , 321 , 322 , 323 , 324 , 325 , 326 ].…”

“…The development of allosteric inverse agonists and neutral antagonists for TSHR is necessary for the treatment of autoimmune hyperthyroidism (Graves’ disease) and associated ophthalmopathy, as well as for the treatment of thyroid cancer caused by activating mutations in TSHR [ 318 , 323 , 326 ]. In 2008, the compound NIDDK/CEB-52 was developed with the activity of a neutral TSHR antagonist in the phenyl ring of which a methoxypropylene group was introduced to facilitate penetration into the transmembrane allosteric site of the receptor [ 344 ].…”

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

“…At the same time, these sites are targets for synthetic low molecular weight compounds, which, through allosteric mechanisms, can regulate the intrinsic and hormone-stimulated activity of TSHR (Figure 3). At present, significant progress has been made both in the study of the configuration of TSHR transmembrane allosteric sites and in the development of small compounds that can bind to them and demonstrate the activity of allosteric regulators and modulators [314][315][316][317][318][319][320][321][322][323][324][325].…”

“…The development of allosteric inverse agonists and neutral antagonists for TSHR is necessary for the treatment of autoimmune hyperthyroidism (Graves' disease) and associated ophthalmopathy, as well as for the treatment of thyroid cancer caused by activating mutations in TSHR [315,322,325]. In 2008, the compound NIDDK/CEB-52 was developed with the activity of a neutral TSHR antagonist, in the phenyl ring of which a methoxypropylene group was introduced to facilitate penetration into the transmembrane allosteric site of the receptor [343].…”