Allosteric Regulators of the Thyroid-Stimulating Hormone Receptor: New Horizons in the Pharmacology of Thyroid Pathology

The thyroid-stimulating hormone receptor (TSHR) expressed in the thyroid gland is a key component of the TSH-regulated signaling system, responsible for the synthesis of thyroid hormones, as well as the growth and proliferation of thyroid cells. TSHR is also present in some non-thyroid tissues (bone tissue, orbital fibroblasts, etc.), controlling their physiological functions. It has a large ectodomain containing a high-affinity orthosteric site that binds TSH and TSHR autoantibodies, as well as a transmembrane domain containing a significant number of allosteric sites with different localizations. TSH-induced TSHR activation triggers multiple signaling cascades mediated by various types of G proteins and β-arrestins. The activation selectivity and efficiency of these cascades are largely determined by allosteric mechanisms, which include the formation of TSHR complexes, the effect on TSH signaling of the “internal” agonist localized at the C-terminus of the TSHR ectodomain hinge region, and TSH N-glycosylation status. Although changes in TSHR activity cause numerous thyroid diseases and other pathologies, TSHR regulators are currently almost not used in clinical medicine. Other therapeutic options do not target TSHR directly, which is associated with many of their side effects. Since the use of TSHR orthosteric site ligands carries significant risks, researchers focus on the ligands of its allosteric sites, including those localized in the transmembrane channel. These ligands have a wide profile of pharmacological activity, including regulators with their own activity (direct and inverse agonists, neutral antagonists), modulators of TSH effects (PAM, NAM, SAM, BAM), and regulators with combined activity (ago-PAM, ago-NAM). Moreover, allosteric ligands are endowed with moderate activity without causing TSHR hyperactivation or complete blockade, in many cases demonstrate selectivity for certain signaling cascades, and retain activity upon oral administration. Therefore, they can be used to treat various thyroid diseases, including Graves’ disease, Hashimoto’s thyroiditis, primary hypothyroidism, thyroid adenomas and cancer, as well as Graves’ ophthalmopathy and musculoskeletal disorders. The review systematizes and analyzes data on low-molecular-weight allosteric regulators of TSHR developed in our laboratory and by other authors, and assesses the prospects for their clinical application.