title: Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones.
abstract: A series of 1,3,4-oxadiazol-2-ones was synthesized and tested for activity as antagonists at GPR55 in cellular beta-arrestin redistribution assays. The synthesis was designed to be modular in nature so that a sufficient number of analogues could be rapidly accessed to explore initial structure-activity relationships. The design of analogues was guided by the docking of potential compounds into a model of the inactive form of GPR55. The results of the assays were used to learn more about the binding pocket of GPR55. With this oxadiazolone scaffold, it was determined that modification of the aryl group adjacent to the oxadiazolone ring was often detrimental and that the distal cyclopropane was beneficial for activity. These results will guide further exploration of this receptor.
authors.affiliation: Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Meza-Aviña
authors.affiliation: Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Lingerfelt
authors.affiliation: Center for Substance Abuse Research, Temple University, Philadelphia, Pennsylvania 19140, United States.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Console-Bram
authors.affiliation: Center for Substance Abuse Research, Temple University, Philadelphia, Pennsylvania 19140, United States.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gamage
authors.affiliation: Center for Substance Abuse Research, Temple University, Philadelphia, Pennsylvania 19140, United States.
authors.forename: Haleli
authors.initials: H
authors.lastname: Sharir
authors.affiliation: Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Gettys
authors.affiliation: Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.
authors.forename: Dow P
authors.initials: DP
authors.lastname: Hurst
authors.affiliation: Department of Chemistry, University of Texas - Pan American, Edinburg, Texas 78539, United States.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Kotsikorou
authors.affiliation: Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Shore
authors.affiliation: Duke University Medical Center, Durham, North Carolina 27709, United States.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.affiliation: Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.
authors.forename: Narasinga
authors.initials: N
authors.lastname: Rao
authors.affiliation: Duke University Medical Center, Durham, North Carolina 27709, United States.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Barak
authors.affiliation: Center for Substance Abuse Research, Temple University, Philadelphia, Pennsylvania 19140, United States.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Abood
authors.affiliation: Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Reggio
authors.affiliation: Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Croatt
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D016466:CHO Cells; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000071557:beta-Arrestins
chemical_list: C586624:1,3,4-oxadiazol-2(3H)-one; D019390:Arrestins; C524885:GPR55 protein, human; D010069:Oxadiazoles; D010880:Piperidines; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins
keywords: Antagonist; Cancer; GPCR; GPR55; Neuropathic pain