title: Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β₂-adrenergic receptor.
abstract: The β₂-adrenergic receptor (β₂-AR) agonist [(3)H]-(R,R')-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (Ki values) of the stereoisomers of a series of 4'-methoxyfenoterol analogs in which the length of the alkyl substituent at α' position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [(3)H]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC₅₀ values, were determined in HEK293 cells expressing the β₂-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the α' position. The results also indicate that the Ki values obtained using [(3)H]-(R,R')-methoxyfenoterol as the marker ligand modeled the EC₅₀ values obtained from cAMP stimulation better than the data obtained using [(3)H]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the β₂-AR conformation probed by [(3)H]-(R,R')-4'-methoxyfenoterol. The CoMFA model of the agonist-stabilized β₂-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the β₂-AR is governed to a greater extend by steric effects than binding to the [(3)H]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role.
authors: Medical University of Lublin, Lublin, Poland.
authors: Anita
authors: A
authors: Plazinska
authors: Medical University of Lublin, Lublin, Poland.
authors: Karolina
authors: K
authors: Pajak
authors: Medical University of Lublin, Lublin, Poland.
authors: Ewelina
authors: E
authors: Rutkowska
authors: SRI International, Menlo Park, CA, United States.
authors: Lucita
authors: L
authors: Jimenez
authors: SRI International, Menlo Park, CA, United States.
authors: Joseph
authors: J
authors: Kozocas
authors: SRI International, Menlo Park, CA, United States.
authors: Gary
authors: G
authors: Koolpe
authors: SRI International, Menlo Park, CA, United States.
authors: Mary
authors: M
authors: Tanga
authors: Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, United States.
authors: Lawrence
authors: L
authors: Toll
authors: Laboratory of Clinical Investigation, National Institute on Aging Intramural Research Program, Baltimore, MD, United States.
authors: Irving W
authors: IW
authors: Wainer
authors: Medical University of Lublin, Lublin, Poland. Electronic address: krzysztof.jozwiak@umlub.pl.
authors: Krzysztof
authors: K
authors: Jozwiak
mesh_terms: D005280:Fenoterol / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; C550094:methoxyfenoterol; D005280:Fenoterol
keywords: Agonist-stabilized conformations; Antagonist-stabilized conformations; [(3)H]-(R,R′)-4′-methoxyfenoterol; β(2)-Adrenoceptor conformations; β(2)-Adrenoceptor selective agonist