Update in TSH receptor agonists and antagonists

Abstract

The physiological role of the TSH receptor (TSHR) as a major regulator of thyroid function is well understood, but TSHRs are also expressed in multiple normal extrathyroidal tissues, and the physiological roles of TSHRs in these tissues are unclear. Moreover, TSHRs play a major role in several pathological conditions including hyperthyroidism, hypothyroidism, and thyroid tumors. Small molecule, "drug-like" TSHR agonists, neutral antagonists, and inverse agonists may be useful as probes of TSHR function in extrathyroidal tissues and as leads to develop drugs for several diseases of the thyroid. In this Update, we review the most recent findings regarding the development and use of these small molecule TSHR ligands.

Fig. 1.

Effects on receptor signaling by agonists, neutral antagonists, and inverse agonists. Control illustrates signaling in the absence of neutral antagonists or inverse agonists. Basal signaling, which represents agonist-independent (or constitutive) signaling, is set as 100. (TSHR is a receptor that exhibits significant basal signaling activity.) Antagonist is a general term that includes neutral antagonists and inverse agonists, which have also been named negative antagonists.

Fig. 2.

Domains of binding to TSHR of TSH, TSAbs, and SMLs. TSHR, like the receptors for FSH and LH, has a large amino-terminal ectodomain that protrudes from the surface of the cells. TSH and TSAbs bind primarily to the TSHR ectodomain. By contrast, SMLs bind to a pocket within the transmembrane domain, which contains the seven α-helical bundles that are characteristic of GPCRs. Ectodomain, Red. Ntt shows the amino terminus of TSHR. Transmembrane domain: Individual helices are ribbons in different colors. The terminal part of the intracellular carboxyl tail (Ctt) is not shown. This model was kindly provided by Gunnar Kleinau, Ph.D., Charité Campus Virchow Klinikum, Berlin, Germany.

Fig. 3.

Structures of TSHR SMLs. TSHR agonist: NCGC00161870, N-(4-(5-(3-benzyl-5-hydroxy-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)-2-methoxybenzyloxy)-phenyl)acetamide. TSHR neutral antagonist: NCGC00242595, 2-(3-((2,6-dimethylphenylthio)methyl)-4-methoxyphenyl)-3-(furan-2-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one. TSHR inverse agonists: NCGC00161856, 2-(3-((2,6-dimethylphenoxy)methyl)-4-methoxyphenyl)-3-(furan-2-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one]; NCGC00229600, 2-(3-((2,6-dimethylphenoxy)methyl)-4-methoxyphenyl)-3-(pyridin-3-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one; and Org 274179-0, (S)-N-(1-acetyl-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-3-(3-trifluoromethyl-phenyl)-propionamide.

Fig. 4.

Inhibition of basal and TSAb-induced up-regulation of the expression of thyroperoxidase mRNA in primary cultures of human thyrocytes. NCGC00229600 inhibited the levels by 65 ± 2.0% (mean ± sem). Importantly, although the thyrocytes were exposed to NCGC00229600 for 48 h, there was no evidence of toxicity. [Reproduced from S. Neumann et al.: A new small-molecule antagonist inhibits Graves' disease antibody activation of the TSH receptor. J Clin Endocrinol Metab 96:548–554, 2011 (36), with permission. © The Endocrine Society.]