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