Characterization of Novel Agonists and Antagonists for Ectopically Expressed Olfactory Receptor OR51E1

Abstract ID 94695 Poster Board 283 Olfactory receptors (ORs) comprise a large family of Class A G protein-coupled receptors (GPCRs); in fact, they represent about half of all known human GPCRs. Upon their discovery in the nasal epithelium, ORs were initially thought to solely mediate the sense of smell. However, their expression has since been found in various tissues and organs, influencing numerous physiological processes. Our lab focuses on OR51E1, one of the few deorphanized ORs known to play a role in blood pressure regulation and highly upregulated in malignant prostate cancer. This specific OR stands out due to its unusually high conservation (95%) among humans and other mammals, suggesting a crucial function. Our recent high-throughput screen (HTS) identified approximately 100 novel small molecules that increased cAMP in an OR51E1-dependent manner. The EC50s of these putative agonists are 10-500 times lower than butyrate, the originally identified ligand of OR51E1. Our initial screen also revealed several antagonists with distinct structures from the agonist chemotypes. Currently, we are characterizing these new chemicals in terms of their mechanism of action on OR51E1. One direction of our research aims to unravel the downstream pathways activated by OR51E1 in human prostate cancer cell lines LNCaP and HEK293, utilizing TRUPATH and other signaling assays. Another aspect of our research investigates the impact of OR51E1 activation on cell behavior and in vivo. Specifically, we found that some agonists inhibit LNCaP cell growth proliferation in 2D and 3D cultures, while other putative agonists have no effect; there are also effects on cell migration in the transwell assay. Concurrently, our in vivo studies concentrate on Olfr558, the mouse homolog of OR51E1, and its sex-dependent regulation of blood pressure, which is performed using telemetry in un-anesthetized mice. Collectively, our efforts underscore the potential use of novel small molecule probes to elucidate the functions of ectopically expressed ORs, offering promising prospects for their development into therapeutic interventions.