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Analogues of Dehydroacetic Acid as Selective and Potent Agonists of an Ectopic Odorant Receptor through a Combination of Hydrophilic and Hydrophobic Interactions
- Analogues of Dehydroacetic Acid as Selective and Potent Agonists of an Ectopic Odorant Receptor through a Combination of Hydrophilic and Hydrophobic Interactions
- Park, Bernie Byunghoon; Lee, NaHye; Kim, YunHye; Jae, YoonGyu; Choi, Seunghyun; Kang, NaNa; Hong, Yu Ri; Ok, Kiwon; Cho, Jeonghee; Jeon, Young Ho; Lee, Eun Hee; Byun, Youngjoo; Koo, JaeHyung
- DGIST Authors
- Koo, JaeHyung
- Issue Date
- Chemmedchem, 12(7), 477-482
- Article Type
- Activation; Agonists; Animal; Animals; Binding Site; Binding Sites; Bladder; Cell Line; Cell Motion; Cell Movement; Cells; Chemical Phenomena; Chemistry; Dehydroacetic Acid; Drug Effects; Expression; Genes, Reporter; Genetics; Hydrogen Bond; Hydrogen Bonding; Hydrophobic And Hydrophilic Interactions; Ligand; Ligands; Metabolism; Molecular Basis; Molecular Docking; Molecular Docking Simulation; Mouse Olfactory Receptor; Mutagenesis, Site Directed; Odorant Receptors; Olfactory Bulb; Olfactory Receptor; Olfr895; Pathology; Protein Coupled Receptor; Protein Structure, Tertiary; Protein Tertiary Structure; Pyrone Derivative; Pyrones; Receptors, Odorant; Repertoire; Reporter Gene; Site Directed Mutagenesis; Structural Basis; Structure Activity Relation; Structure Activity Relationship; Synthesis; Urinary Bladder
- Identification of potent agonists of odorant receptors (ORs), a major class of Gprotein-coupled receptors, remains challenging due to complex receptor-ligand interactions. ORs are present in both olfactory and non-chemosensory tissues, indicating roles beyond odor detection that may include modulating physiological functions in non-olfactory tissues. Selective and potent agonists specific for particular ORs can be used to investigate physiological functions of ORs in non-chemosensory tissues. In this study, we designed and synthesized novel synthetic dehydroacetic acid analogues as agonists of odorant receptor 895 (Olfr895) expressed in bladder. Among the synthesized analogues, (E)-3-((E)-1-hydroxy-3-(piperidin-1-yl)allylidene)-6-methyl-2H-pyran-2,4(3H)-dione (10) exhibited extremely high agonistic activity for Olfr895 in Dual-Glo luciferase reporter (EC50=9nm), Ca2+ imaging, and chemotactic migration assays. Molecular docking and site-directed mutagenesis studies suggested that a combination of hydrophilic and hydrophobic interactions is central to the selective and specific binding of 10 to Olfr895. The design of agonists armed with both hydrophilic and hydrophobic portions could therefore lead to highly potent and selective ligands for ectopic ORs.
- Wiley-VCH Verlag
- Related Researcher
Koo, Jae Hyung
The Koo Lab - ChemoReception Laboratory(CRLab)
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- Brain and Cognitive SciencesThe Koo Lab - ChemoReception Laboratory(CRLab)1. Journal Articles
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