Development of orally active agonists of the TSH receptor

TOPIC: TSH receptor

Title: Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice.

Authors: Neumann S, Huang W, Titus S, Krause G, Kleinau G, Alberobello AT, Zheng W, Southall NT, Inglese J, Austin CP, Celi FS, Gavrilova O, Thomas CT, Raaka BM, & Gershengorn MC .

Reference: Proc. Natl. Acad. Sciences 106: 12471–12476, 2009



Seven-transmembrane-spanning receptors (7TMRs or GPCRs) are prominent drug targets. However, small-molecule ligands for 7-transmembrane-spanning receptors for which the natural ligands are large heterodimeric glycoprotein hormones, like TSH, have only recently been reported, and none are approved for human use.


The authors have used quantitative high-throughput screening to identify a small-molecule TSH receptor (TSHR) agonist that was modified to produce a second agonist with increased potency.


The study shows that these agonists are highly selective for the human TSHR versus other glycoprotein hormone receptors and interact with the receptor’s serpentine domain. A binding pocket within the transmembrane domain was defined by docking into a TSHR homology model and was supported by site-directed mutagenesis. In primary cultures of human thyrocytes, both TSH and the agonists increased mRNA levels for thyroglobulin, thyroperoxidase, sodium iodide symporter, and deiodinase type 2, and deiodinase type 2 enzyme activity. Moreover, oral administration of the agonist stimulated thyroid function in mice, resulting in increased serum thyroxine and thyroidal uptake of radioiodine.


A small molecule that activates the human TSHR in vitro has been identified. It is orally active in mice and could be a lead for development of drugs to use in place of recombinant human TSH in patients with thyroid cancer.


GPCRs constitute one of the largest multigenic families in the human genome. They are implicated in the control of virtually all physiological functions, which explains their success as pharmacological targets. Major drugs, active e.g. in the treatment of schizophrenia, allergy, hypertension, gastric ulcer, pain, benign prostate hypertrophy and even HIV, belong to a subfamily of GPCRs evolutionary and structurally related to rhodopsin.

In the majority of cases, these drugs are small chemical molecules mimicking or antagonizing the effects of the natural agonists which are themselve small bioactive molecules (noradrenaline, acethylcholine, histamine, dopamine…). There are, however, subfamilies of GPCRs recognizing polypeptides (neuropeptides, chemokines..) or even large hormones (TSH, LH/hCG, FSH). In the case of glycoprotein hormones, the receptors can be viewed as bi-functional structures with an ectodomain specialized in hormone binding, and a rhodopsin-like membrane spanning domain involved in transducing the signal to intracellular regulatory cascades. Conceptually, it is therefore difficult to develop molecules mimicking the effects of large hormones by binding to the ectodomain.

The group of Marvin Gershengorn has solved this problem by using the ‘global’ approach followed in pharmaceutical companies, namely the screening of large chemical libraries (73.180 in this case), using as endpoint activation of a cAMP-gated cation channel in a cell line expressing the TSH receptor. This approach has the advantage of allowing detection of an agonist, irrespective of the way it activates the receptor. Optimization of the candidates involved further screening of analogues obtained by chemical derivatization. Potential applications of this study are evident: development of orally active TSHR agonists which could replace recombinant TSH in its application. A similar approach aiming at identification of antagonists or inverse agonists (molecules capable of reducing the activity of constitutively active receptor mutants) would lead to compounds active in the treatment of Graves’disease, toxic adenoma and non-autoimmune toxic thyroid hyperplasia.

From a fundamental point of view, identification of the sites of interaction between the compounds [(inverse) agonists and antagonists] and the receptor contributes to our understanding of the mechanism implicated in the activation of the TSHR and GPCRs. Summary and Commentary prepared by Gilbert Vassart (Related to Chapter 1 of TDM)