Fenoterol derivatives show multitarget interactions with beta2 adrenergic and 5‐HT receptors

Abstract

Stereoisomers of fenoterol and eight fenoterol derivatives modified at the N‐alkyl moiety (Fig. 1) have been synthesized to determine their binding affinities for the β2 adrenergic receptor (β2–AR) and the subtype selectivity relative to the β1–AR. Sub‐micromolar affinities were observed for (R,R)‐fenoterol, the (R,R) isomer of the p‐methoxy, (R,R) and (R,S) isomers of 1‐naphthyl and (R,R) and (R,S) isomers 4‐methoxy‐1‐napthyl derivatives. Most of these compounds show also high β2/β1 subtype selectivity. Off‐target screening panel revealed that some naphtyl derivatives show additional high binding affinities towards 5‐HT2 and 5‐HT3 subtypes of serotonin receptor determined in radioligand displacement assays.The binding data were analyzed using 3‐D QSAR and the resulting pseudo‐receptor models identified binding fields responsible for asymmetric recognition of diastereoisomers. The steric restriction on the second chiral center is responsible for observed β2/β1 subtype selectivity. Molecular models of β2‐AR and β1‐AR macromolecules were used to analyze ligand‐receptor interactions. Docking and molecular dynamics simulations on the β2‐AR model revealed that S204, S207 and T118 residues form the network of hydrogen bonds interacting with the catechol moiety; residues N293 and D113 mainly affect the asymmetric recognition of diastereoisomers and T308 and H296 residues are responsible for β2/β1 subtype selectivity profile of studied compounds. Molecular modeling investigations of ligand interactions with serotonin receptors were also performed.The data from the binding and modeling studies indicate that this set of compounds can be used to explore a wide variety of ligand‐GPCR binding mechanisms.