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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

Title
Analogues of Dehydroacetic Acid as Selective and Potent Agonists of an Ectopic Odorant Receptor through a Combination of Hydrophilic and Hydrophobic Interactions
Authors
Park, Bernie ByunghoonLee, NaHyeKim, YunHyeJae, YoonGyuChoi, SeunghyunKang, NaNaHong, Yu RiOk, KiwonCho, JeongheeJeon, Young HoLee, Eun HeeByun, YoungjooKoo, JaeHyung
DGIST Authors
Koo, JaeHyung
Issue Date
2017-04
Citation
Chemmedchem, 12(7), 477-482
Type
Article
Article Type
Article
Keywords
ActivationAgonistsAnimalAnimalsBinding SiteBinding SitesBladderCell LineCell MotionCell MovementCellsChemical PhenomenaChemistryDehydroacetic AcidDrug EffectsExpressionGenes, ReporterGeneticsHydrogen BondHydrogen BondingHydrophobic And Hydrophilic InteractionsLigandLigandsMetabolismMolecular BasisMolecular DockingMolecular Docking SimulationMouse Olfactory ReceptorMutagenesis, Site DirectedOdorant ReceptorsOlfactory BulbOlfactory ReceptorOlfr895PathologyProtein Coupled ReceptorProtein Structure, TertiaryProtein Tertiary StructurePyrone DerivativePyronesReceptors, OdorantRepertoireReporter GeneSite Directed MutagenesisStructural BasisStructure Activity RelationStructure Activity RelationshipSynthesisUrinary Bladder
ISSN
1860-7179
Abstract
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.
URI
http://hdl.handle.net/20.500.11750/5011
DOI
10.1002/cmdc.201600612
Publisher
Wiley-VCH Verlag
Related Researcher
  • Author Koo, Jae Hyung The Koo Lab - ChemoReception Laboratory(CRLab)
  • Research Interests
Files:
There are no files associated with this item.
Collection:
Brain and Cognitive SciencesThe Koo Lab - ChemoReception Laboratory(CRLab)1. Journal Articles


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