{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T07:30:36Z","timestamp":1791099036525,"version":"4.1.0"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"30","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,7,28]]},"abstract":"<jats:p>Seven-transmembrane-spanning receptors (7TMRs) are prominent drug targets. However, small-molecule ligands for 7-transmembrane-spanning receptors for which the natural ligands are large, heterodimeric glycoprotein hormones, like thyroid-stimulating hormone (TSH; thyrotropin), have only recently been reported, and none are approved for human use. We 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. We show that these agonists are highly selective for 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 increase 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 radioiodide uptake. Thus, we discovered a small molecule that activates human TSHR in vitro, 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.<\/jats:p>","DOI":"10.1073\/pnas.0904506106","type":"journal-article","created":{"date-parts":[[2009,7,10]],"date-time":"2009-07-10T20:34:27Z","timestamp":1247258067000},"page":"12471-12476","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":100,"title":["Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice"],"prefix":"10.1073","volume":"106","author":[{"given":"Susanne","family":"Neumann","sequence":"first","affiliation":[{"name":"Clinical Endocrinology Branch and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwei","family":"Huang","sequence":"additional","affiliation":[{"name":"National Institutes of Health Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Titus","sequence":"additional","affiliation":[{"name":"National Institutes of Health Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerd","family":"Krause","sequence":"additional","affiliation":[{"name":"Leibniz-Institut f\u00fcr Molekulare Pharmakologie, D-13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Kleinau","sequence":"additional","affiliation":[{"name":"Leibniz-Institut f\u00fcr Molekulare Pharmakologie, D-13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Teresa","family":"Alberobello","sequence":"additional","affiliation":[{"name":"Clinical Endocrinology Branch and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zheng","sequence":"additional","affiliation":[{"name":"National Institutes of Health Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noel T.","family":"Southall","sequence":"additional","affiliation":[{"name":"National Institutes of Health Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Inglese","sequence":"additional","affiliation":[{"name":"National Institutes of Health Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P.","family":"Austin","sequence":"additional","affiliation":[{"name":"National Institutes of Health Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco S.","family":"Celi","sequence":"additional","affiliation":[{"name":"Clinical Endocrinology Branch and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oksana","family":"Gavrilova","sequence":"additional","affiliation":[{"name":"Mouse Metabolism Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig J.","family":"Thomas","sequence":"additional","affiliation":[{"name":"National Institutes of Health Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce M.","family":"Raaka","sequence":"additional","affiliation":[{"name":"Clinical Endocrinology Branch and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin C.","family":"Gershengorn","sequence":"additional","affiliation":[{"name":"Clinical Endocrinology Branch and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,7,28]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"24","article-title":"It's a GPCR world","volume":"11","author":"Filmore D","year":"2004","unstructured":"D Filmore, It's a GPCR world. 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