title: Analogues of Dehydroacetic Acid as Selective and Potent Agonists of an Ectopic Odorant Receptor through a Combination of Hydrophilic and Hydrophobic Interactions.
abstract: Identification of potent agonists of odorant receptors (ORs), a major class of G protein-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=9 nm), 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.
authors.affiliation: College of Pharmacy, Korea University, Sejong, 30019, South Korea.
authors.forename: Bernie Byunghoon
authors.initials: BB
authors.lastname: Park
authors.affiliation: Department of Brain and Cognitive Sciences, DGIST, Daegu, 42988, South Korea.|Department of New Biology, DGIST.
authors.forename: NaHye
authors.initials: N
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Korea University, Sejong, 30019, South Korea.
authors.forename: YunHye
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Brain and Cognitive Sciences, DGIST, Daegu, 42988, South Korea.|Department of New Biology, DGIST.
authors.forename: YoonGyu
authors.initials: Y
authors.lastname: Jae
authors.affiliation: College of Pharmacy, Korea University, Sejong, 30019, South Korea.
authors.forename: Seunghyun
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of New Biology, DGIST.
authors.forename: NaNa
authors.initials: N
authors.lastname: Kang
authors.affiliation: Department of New Biology, DGIST.
authors.forename: Yu Ri
authors.initials: YR
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Korea University, Sejong, 30019, South Korea.
authors.forename: Kiwon
authors.initials: K
authors.lastname: Ok
authors.affiliation: Department of NanoBio Medical Science, Dankook University, Cheonan, 31116, South Korea.
authors.forename: Jeonghee
authors.initials: J
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Korea University, Sejong, 30019, South Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Jeon
authors.affiliation: College of Pharmacy, Korea University, Sejong, 30019, South Korea.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Korea University, Sejong, 30019, South Korea.
authors.forename: Youngjoo
authors.identifier: 0000-0002-0297-7734
authors.initials: Y
authors.lastname: Byun
authors.affiliation: Department of Brain and Cognitive Sciences, DGIST, Daegu, 42988, South Korea.|Department of New Biology, DGIST.
authors.forename: JaeHyung
authors.initials: J
authors.lastname: Koo
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D017930:Genes, Reporter; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D016297:Mutagenesis, Site-Directed; D009830:Olfactory Bulb / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018035:Receptors, Odorant / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology
chemical_list: D008024:Ligands; D011753:Pyrones; D018035:Receptors, Odorant; C027493:dehydroacetic acid
keywords: agonists; dehydroacetic acid; odorant receptors; olfr895