Basic Information

Abstract Number: 250 - 5
Author Name: Krzysztof Jozwiak - Medical University of Lublin
Session Title: Chromatography Forum of the Delaware Valley Dal Nogare Award
Event Type: Awards
Event Title: Development of New Derivatives of Fenoterol as Potential Ligands of the β2 Adrenergic Receptor with Novel Therapeutic Perspectives

Presider Name:Mary Ellen McNallyCo-Author:Anita Plazinska, Karolina Pajak, Ewelina Rutkowska, Lawrence Toll, Lucita Jimenez, Irving W Wainer
Affiliation:DuPont Crop ProtectionAffiliation:Medical University of Lublin, Torrey Pines Institute for Molecular Studies, SRI International, National Institute of Health

Date: Monday, March 18, 2013
Start Time: 09:20 AM (Slot #5)
Location: 126A

Abstract Content

Fenoterol (FEN), a β2-AR selective agonist is used in asthma therapy as (R,R)- and (S,S)-racemate. Rational drug design approach were employed to develop a number of FEN derivatives and stereoisomers. The β2-AR radioligand displacement studies evidenced significantly different binding affinities towards inactive and active forms of the receptor. Van’t Hoff analysis the data showed that the thermodynamics of complex formation highly depends of the stereochemistry of FEN. The compounds were widely tested functionally. The results shows that stereochemistry of a molecule affected the coupling properties of the receptor to different G proteins upon agonist binding. In cardiomyocyte contractility studies, the addition of pertussis toxin has no effect on activity of (R,R)-FEN, (R,R)-4-methoxyFEN and (R,R)-4-aminoFEN, indicating that the receptor selectively couples Gs protein signaling upon binding of these compounds. Conversely, pertussis toxin significantly affected cellular effects elicited by (R,R)-1-naphtylFEN and (R,R)-4-methoxy-1-naphtylFEN, showing that binding activates the receptor to forms able to couple both Gs and Gi. Molecular modeling simulations of binding to the β2-AR models linked this difference with different interactions of derivatives with Y308 residue of β2-AR model. Subsequent studies on β2-AR Y308A mutant confirmed that binding affinities of Gs selective derivatives are significantly reduced comparing to the β2-AR WT data, while Y308A mutation did not affect affinities of ligands inducing both Gs and Gi signaling.
The overall data demonstrate that stereochemistry and chemical constitution of a FEN derivative influence magnitude of binding affinity, thermodynamics of local ligand - receptor interactions and the global mechanism of β2-AR activation. This medicinal chemistry project opens new perspectives for development of novel potent and highly selective β2-AR agonists for treatment of congestive heart failure or brain tumors.