{"id":1238,"date":"2026-01-24T08:35:20","date_gmt":"2026-01-24T08:35:20","guid":{"rendered":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/2026\/01\/24\/a-low-molecular-weight-antagonist-prevents-tsh-and-antibody-induced-activation-of-the-human-thyrotro\/"},"modified":"2026-01-24T08:35:20","modified_gmt":"2026-01-24T08:35:20","slug":"a-low-molecular-weight-antagonist-prevents-tsh-and-antibody-induced-activation-of-the-human-thyrotro","status":"publish","type":"post","link":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/2026\/01\/24\/a-low-molecular-weight-antagonist-prevents-tsh-and-antibody-induced-activation-of-the-human-thyrotro\/","title":{"rendered":"A LOW MOLECULAR WEIGHT ANTAGONIST PREVENTS TSH- AND ANTIBODY-INDUCED ACTIVATION OF THE HUMAN THYROTROPIN RECEPTOR"},"content":{"rendered":"
Krause G.1<\/sup>, Neumann S.2<\/sup>, Kleinau G.1<\/sup>, Costanzi S.2<\/sup>, Moore S.2<\/sup>, Jiang J.3<\/sup>, Raaka B. M.2<\/sup>, Thomas J. C.3<\/sup>, Gershengorn C. M.2<\/sup><\/div>\n
1<\/sup>Leibniz-Institut f?r Molekulare Pharmakologie, Berlin, Germany, 2<\/sup>National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA, 3<\/sup>NIH Chemical Genomics Center, National Human Genome Research Institute, Bethesda, MD, USA<\/div>\n
\n

Abstract<\/h2>\n

The thyroid-stimulating hormone receptor (TSHR) is the target of stimulating antibodies in Graves hyperthyroidism. Orally active low molecular weight (LMW) antagonists may have therapeutic potential by antagonizing stimulating antibodies in these patients. The thienopyrimidine Org41841 was identified by others as a partial agonist for the luteinizing hormone\/chorionic gonadotropin receptor and we showed previously that this ligand also activates TSHR by allosteric binding in a pocket within the TSHR transmembrane core.
Applying a structure-based rational approach by using the agonistic compound as initial template, we now designed a number of new analogs. Extensive molecular docking studies revealed key interactions between the analogs and the receptor that were supported by site-directed mutagenesis of TSHR. Among the analogs supposed to interfere with TSHR activation, the synthesized compound 52 was found to be a moderately potent antagonist of TSH and antibody stimulation of TSHR without exhibiting agonistic activity at TSHR.
Our molecular model appears to explain the pharmacological profile of these analogs by predicting that compound 52 presumably acts as an antagonist by preventing critical contacts with residues deeper in the transmembrane pocket that are known to be important for agonist activity. Thus it occupies the transmembrane binding pocket differently than the agonists without itself promoting or allowing the structural changes required for receptor activation.
Our findings of a potential molecular inhibition mechanism and the identified compound establish both a base and lead for the development of higher potency TSHR antagonists that may have therapeutic potential for the treatment of Graves hyperthyroidism. Finally, our results serve as “proof-of-principle” that LMW ligands that target the transmembrane region of the TSHR might serve as drugs in patients.<\/div>\n","protected":false},"excerpt":{"rendered":"

Krause G.1, Neumann S.2, Kleinau G.1, Costanzi S.2, Moore S.2, Jiang J.3, Raaka B. M.2, Thomas J. C.3, Gershengorn C. M.2 1Leibniz-Institut f?r Molekulare Pharmakologie, Berlin, Germany, 2National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA, 3NIH Chemical Genomics Center, National Human Genome Research Institute, Bethesda, MD, USA Abstract The thyroid-stimulating Read More<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[45,2,9],"tags":[],"class_list":["post-1238","post","type-post","status-publish","format-standard","hentry","category-volume-7-issue-3","category-journal-articles","category-volume-7"],"_links":{"self":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts\/1238","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/comments?post=1238"}],"version-history":[{"count":0,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts\/1238\/revisions"}],"wp:attachment":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/media?parent=1238"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/categories?post=1238"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/tags?post=1238"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}