Structural basis of the selectivity of the beta(2)-adrenergic receptor for fluorinated catecholamines.
The important and diverse biological functions of adrenergic receptors, a subclass of G protein-coupled receptors (GPCRs), have made the search for compounds that selectively stimulate or inhibit the activity of different adrenergic receptor subtypes an important area of medicinal chemistry. We previously synthesized 2-, 5-, and 6-fluoronorepinehprine (FNE) and 2-, 5-, and 6-fluoroepinephrine (FEPI) and found that 2FNE and 2FEPI were selective beta-adrenergic agonists and that 6FNE and 6FEPI were selective alpha-adrenergic agonists, while 5FNE and 5FEPI were unselective. Agonist potencies correlated well with receptor binding affinities. Here, through a combination of molecular modeling and site-directed mutagenesis, we have identified N293 in the beta(2)-adrenergic receptor as a crucial residue for the selectivity of the receptor for catecholamines fluorinated at different positions.
Pooput
Chaya
C
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
Rosemond
Erica
E
Karpiak
Joel
J
Deflorian
Francesca
F
Vilar
Santiago
S
Costanzi
Stefano
S
Wess
Jürgen
J
Kirk
Kenneth L
KL
D001667:Binding, Competitive / Q000502:physiology; D004837:Epinephrine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009638:Norepinephrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017354:Point Mutation / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D018343:Receptors, Adrenergic, beta-2; D009638:Norepinephrine; D004837:Epinephrine