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• W4377029088 abstract "<b>Abstract ID 16032</b> <b>Poster Board 554</b> Olfactory receptors (ORs) were originally discovered in the nasal epithelium, where they mediate the sense of smell. However, members of this very large family of GPCRs (∼400 genes in humans and ∼1,200 in mice) were subsequently found in airways, blood vessels, gut and other tissues. These ORs are referred to as ectopically expressed ORs or “ectopic ORs”. Some current evidence indicates that they are involved in sensing metabolites, cell signaling and/or other functions of ORs remain enigmatic. There are several technical obstacles that have been impeding progress in OR investigation for decades. These difficulties include the need for special chaperones necessary for OR trafficking and expression in the functional form, absence of anti-OR antibodies and lack of effective pharmacological tools. Here, we will report the results of the first high throughput screen (HTS) for molecular probes for an OR, OR51E1. We focused on this OR for several reasons, e.g., it is highly upregulated in malignant prostate cancer tumors; it was found in a subset of blood vessels and shown to be involved in regulation of blood pressure; it is one of the few ORs that was deorphanized and shown to be activated by butyrate and other short chain fatty acids. Notably, OR51E1 has an unusually high conservation (95%) between humans and other mammals, indicative of its important physiological function. Through our HTS and subsequent hit expansion, we identified ∼100 novel small compound agonists which increase cAMP in a OR51E1-dependent manner, and have the EC50 10-500 times lower than butyrate. We also found several antagonists, which have a structure distinct from the two agonist chemotypes tha we dentified among our hits. These results demonstrate that successful discovery of drug-like compounds targeting ectopically expressed ORs is possible. Our on-going efforts are aimed at characterization of pharmacological properties of the new ligands, downstream signaling, cellular and physiological effects, and structure-function aspects of OR51E1-drug interaction. Since our expression system and hit confirmation pipeline works not only for OR51E1, but alos for other ORs, our platform must be applicable for other members of this vast and untapped Class A GPCR family." @default.
• W4377029088 created "2023-05-19" @default.
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• W4377029088 date "2023-05-18" @default.
• W4377029088 modified "2023-10-18" @default.
• W4377029088 title "Discovery of New Agonists and Antagonists for Ectopically Expressed Olfactory Receptor OR51E1" @default.
• W4377029088 doi "https://doi.org/10.1124/jpet.122.160320" @default.
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