Structural basis of the selectivity of the beta(2)-adrenergic receptor for fluorinated catecholamines.

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Pooput C, Rosemond E, Karpiak J, Deflorian F, Vilar S, Costanzi S, Wess J, Kirk KL

Structural basis of the selectivity of the beta(2)-adrenergic receptor for fluorinated catecholamines.

Bioorg Med Chem. 2009 Dec 1;17(23):7987-92. doi: 10.1016/j.bmc.2009.10.015. Epub 2009 Oct 13.

PubMed ID
19857969 [ View in PubMed
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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 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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
NorepinephrineAlpha-1B adrenergic receptorKi (nM)20400N/AN/ADetails