What question did this study set out to answer?

Determine the molecular pharmacology and inhibitory mechanism of Org 274179-0, a low molecular weight TSH receptor antagonist developed for Graves' disease and thyroid eye disease.

October 21, 2011British Journal of PharmacologyOpen Access

Mechanism of action of a nanomolar potent, allosteric antagonist of the thyroid‐stimulating hormone receptor

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Authors

CKChris J. van KoppenMerck & Co., Inc., Rahway, NJ, USA (United States)MGMarcel E. de GooyerSNV Netherlands Development Organisation WKWillem-Jan F. KarstensMerck (Netherlands)

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Implication

In vitro study uncovers allosteric inhibition of TSH receptors by Org 274179-0, indicating therapeutic potential for Graves' disease.

Key Points

Determine the molecular pharmacology and inhibitory mechanism of Org 274179-0, a low molecular weight TSH receptor antagonist developed for Graves' disease and thyroid eye disease.
Evaluated the potency and efficacy of Org 274179-0 in CHO cells expressing human TSH receptors and rat FRTL-5 cells expressing rat TSH receptors under TSH and TSI stimulation.
Tested cross-reactivity against related follicle-stimulating hormone and luteinizing hormone receptors.
Characterized allosteric receptor interactions and measured inverse agonism across five naturally occurring, constitutively active TSH receptor mutants.
Org 274179-0 fully inhibited both TSH- and TSI-induced receptor signaling at nanomolar concentrations with minimal effect on TSH potency, establishing an allosteric mechanism.
Elevated concentrations of TSH receptor agonists only marginally decreased the antagonist potency of the compound.
The compound acted as an inverse agonist, completely blocking basal signaling across all five constitutively active TSH receptor mutants with nanomolar potencies.

Cite This Study

Koppen et al. (2011) studied this question.

synapsesocial.com/papers/6ab481d74fbe54468a75b68a https://doi.org/10.1111/j.1476-5381.2011.01709.x

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Mechanism of action of a nanomolar potent, allosteric antagonist of the thyroid‐stimulating hormone receptor

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Cite This Study

Mechanism of action of a nanomolar potent, allosteric antagonist of the thyroid‐stimulating hormone receptor

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Implication

Key Points

Cite This Study

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