Structural basis of the selectivity of the β2-adrenergic receptor for fluorinated catecholamines |
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| Authors: | Chaya Pooput Erica Rosemond Joel Karpiak Francesca Deflorian Santiago Vilar Stefano Costanzi Jürgen Wess Kenneth L Kirk |
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| Institution: | 1. Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA;2. Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA |
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| Abstract: | 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 β-adrenergic agonists and that 6FNE and 6FEPI were selective α-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 β2-adrenergic receptor as a crucial residue for the selectivity of the receptor for catecholamines fluorinated at different positions. |
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