β₂ adrenergic receptors (β₂-ARs) belong to the large family of the G protein-coupled receptors (GPCRs). With almost 50–60% of drugs in the market targeting GPCRs, they are the most important family of receptors in the drug discovery field.

We studied stereoisomers of fenoterol (Fig. 1) and its derivatives which are a selective β₂-AR agonists [1,2].

 Fig. 1. Stereoisomers of fenoterol.

 Our studies show the association of molecular structure fenoterol analogs with significant differences in activation patterns of the β₂-AR. The results of the pertussis toxin -controlled (PTx-controlled) myocyte contraction analysis indicate that subtle changes in a chemical constitution of fenoterol derivatives play a decisive role in inducing G_s selective or G_s/G_i (G stimulatory/G inhibitory) patterns of receptor coupling [3]. While (R,R)-isomers of fenoterol, 4-methoxy-fenoterol and 4-amino-fenoterol activate β₂-AR to a form which couples selectively to G_s protein (group A, G_s selective compounds), the receptor activated by e.g. 1-naphtyl-fenoterol or 4-methoxy-1-naphtyl-fenoterol is able to couple uniformly both G_s and G_i proteins (group B, non G_s selective).

Molecular modeling studies show that hydrogen bond (HB) formation between N-alkyl moiety of a ligand with Y308^7.35 is a key interaction distinguishing G_s selective derivatives from others, non selective derivatives. This hypothesis has been positively validated using Y308A mutant of the β₂-AR: G_s selectivity of the mutant is lost in the experiments with (R,R)-fenoterol and (R,R)-4-amino-fenoterol. The Y308A mutant shows significantly reduced affinities for compounds of group A as compared with the wild type-related data (WT β₂-AR). When compounds of group B were tested on the mutant, their binding affinity (K_i) were not affected by Y308A mutation and were very close to those determined for WT β₂-AR.

In addition, docking studies indicate two alternative binding modes of studied compounds interacting with β₂-AR in its binding site. The binding pattern depends on the structure of the N-alkyl part of these derivatives. The molecules containing benzyl ring substituted in the 4’ position with oxygen or nitrogen atom are able to form HB with Y308^7.35 (group A) independently from interactions with the aromatic cleft. These derivatives while in the (R,R)-stereoconfiguration, induce PTx insensitive contractile response. If a derivative contains the naphtyl moiety (group B), the Π-Π interactions with residues forming the aromatic cleft of the receptor seem to be dominated.

 Grant information: NIH/NIA contract N01AG-3-1009 and Foundation for Polish Science grant TEAM 2009-4/5.

 1.      Jóźwiak K, Khalid C, et al., J. Med Chem. 2007;50(12):2903-15.

2.      Jóźwiak K, Woo YH, et al., Bioorg Med Chem 2010;18(2):728-736.

3.      Woo AY, Wang TB, Zeng X, Zhu W, Abernethy DR, Wainer IW, Xiao RP. Mol Pharmacol. 2009;75(1):158-65.

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/28081 must be provided.

1. Differential aspects of molecular interactions fenoterol stereoisomers and derivatives with the β₂-adrenergic receptor
2. Docking Study of fenoterol derivatives to the β₂ adrenergic receptor. Molecular dynamic simulations for selected agonist-β₂-AR complexes.
3. Functional activity of new derivatives of dextromethorphan as allosteric inhibitors of α3β4 nicotinic acetylocholine receptor.
4. Molecular modeling of allosteric modulation of nicotinic acetylcholine receptor by different classes of ligands
5. 3D-QSAR modeling of binding affinities and functional activities for the set of β₂ adrenergic receptor agonists.
6. An old drug with new perspectives: How stereochemistry of fenoterol and fenoterol derivatives influences the β-adrenergic binding and the G-protein coupling selectivity.
7. MOLECULAR INTERACTIONS BETWEEN NICOTINIC ACETYLCHOLINE RECEPTOR AND ITS LIGANDS - CHROMATOGRAPHIC AND MODELING APPROACHES