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.
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
Chaya
C
Pooput
Erica
E
Rosemond
Joel
J
Karpiak
Francesca
F
Deflorian
Santiago
S
Vilar
Stefano
S
Costanzi
Jürgen
J
Wess
Kenneth L
KL
Kirk
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