title: A small molecule inverse agonist for the human thyroid-stimulating hormone receptor.
abstract: Small molecule inverse agonists for the TSH receptor (TSHR) may be used as probes of the role of basal (or agonist-independent or constitutive) signaling and may have therapeutic potential as orally active drugs to inhibit basal signaling in patients with thyroid cancer and in some patients with hyperthyroidism. We describe the first small-molecule ligand [1;2-(3-((2,6-dimethylphenoxy)methyl)-4-methoxyphenyl)-3-(furan-2-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one] that exhibits inverse agonist properties at TSHR. 1 inhibits basal and TSH-stimulated signaling, measured as cAMP production, by TSHRs in HEK-EM 293 cells stably expressing wild-type TSHRs; the antagonism of TSH-mediated signaling is competitive. 1 also inhibits basal signaling by wild-type TSHRs, and four constitutively active mutants of TSHR expressed transiently in HEK-EM 293 cells. 1 was active under more physiologically relevant conditions in primary cultures of human thyrocytes expressing endogenous TSHRs where it inhibited basal levels of mRNA transcripts for thyroglobulin, thyroperoxidase, sodium iodide symporter, and TSHR. These data serve as proof of principle that small, drug-like molecules can inhibit basal signaling by TSHR. We suggest that this small molecule is a lead compound for the development of higher-potency inverse agonists that can be used as probes of TSHR biology with therapeutic potential.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, Clinical Endocrinology Branch, National Institutes of Health, 50 South Drive, Bethesda, Maryland 20892-8029.
authors.forename: Susanne
authors.initials: S
authors.lastname: Neumann
authors.forename: Wenwei
authors.initials: W
authors.lastname: Huang
authors.forename: Elena
authors.initials: E
authors.lastname: Eliseeva
authors.forename: Steve
authors.initials: S
authors.lastname: Titus
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Marvin C
authors.initials: MC
authors.lastname: Gershengorn
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016297:Mutagenesis, Site-Directed; D011989:Receptors, Thyrotropin / Q000819:agonists* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013972:Thyrotropin / Q000494:pharmacology
chemical_list: D011989:Receptors, Thyrotropin; D013972:Thyrotropin; D000242:Cyclic AMP