Comparative Molecular Field Analysis of the Binding of the Stereoisomers of Fenoterol and Fenoterol Derivatives to the β₂ Adrenergic Receptor

Abstract

Stereoisomers of fenoterol and six fenoterol derivatives have been synthesized and their binding affinities for the beta2 adrenergic receptor (Kibeta2-AR), the subtype selectivity relative to the beta1-AR (Kibeta1-AR/Kibeta2-AR) and their functional activities were determined. Of the 26 compounds synthesized in the study, submicromolar binding affinities were observed for (R,R)-fenoterol, the (R,R)-isomer of the p-methoxy, and (R,R)- and (R,S)-isomers of 1-naphthyl derivatives and all of these compounds were active at submicromolar concentrations in cardiomyocyte contractility tests. The Kibeta1-AR/Kibeta2-AR ratios were >40 for (R,R)-fenoterol and the (R,R)-p-methoxy and (R,S)-1-naphthyl derivatives and 14 for the (R,R)-1-napthyl derivative. The binding data was analyzed using comparative molecular field analysis (CoMFA), and the resulting model indicated that the fenoterol derivatives interacted with two separate binding sites and one steric restricted site on the pseudo-receptor and that the chirality of the second stereogenic center affected Kibeta2 and subtype selectivity.

Thermodynamics and Docking of Agonists to the β2-Adrenoceptor Determined Using [3H](R,R′)-4-Methoxyfenoterol as the Marker Ligand

“…The K i values were calculated by the method of Cheng and Prusoff (1973). Table 1) (Jozwiak et al, 2007). The calculated B max value was also lower than the previously reported value, 8901 Ϯ 1161 fmol/mg protein, also determined using [ 3 H]CGP-12177 as the marker ligand (Jozwiak et al, 2007).…”

“…The Fen analogs used in this study (Fig. 1) were synthesized as described previously (Jozwiak et al, 2007), and the preparation of [ 3 H]MFen (25 Ci/mmol; Fig. 1) has been reported (Kozocas et al, 2010 -118-551), Tris-HCl, Trizma base, potassium chloride, magnesium chloride, and D-(ϩ)-glucose were purchased from SigmaAldrich (St. Louis, MO).…”

“…1) (Jozwiak et al, 2007(Jozwiak et al, , 2010aToll et al, 2011). During the course of these studies, we determined the binding thermodynamics of the four stereoisomers of Fen, (R,RЈ)-, (R,SЈ)-, (S,RЈ)-, and (S,SЈ)-Fen to the ␤ 2 -AR (Jozwiak et al, 2010a).…”

Cannabinoid Receptor Activation Correlates with the Proapoptotic Action of the β2-Adrenergic Agonist (R,R′)-4-Methoxy-1-Naphthylfenoterol in HepG2 Hepatocarcinoma Cells

“…(R,RЈ)-, (R,SЈ)-, (S,RЈ)-, and (S,SЈ)-fenoterol and the fenoterol analogs (R,RЈ)-ethylfenoterol, (R,RЈ)-4Ј-aminofenoterol, (R,RЈ)-1-naphthylfenoterol, and (R,RЈ)-and (R,SЈ)-4-methoxy-1-naphthylfenoterol were synthesized as described previously (Jozwiak et al, 2007(Jozwiak et al, , 2010. [ 3 H]thymidine (70 -90 Ci/mmol) was purchased from PerkinElmer Life and Analytical Sciences (Waltham, MA).…”

“…We had reported the synthesis and characterization of a number of Fen analogs and stereoisomers with a range of ␤ 2 -AR selectivity and potency (Jozwiak et al, 2007(Jozwiak et al, , 2010. One of these analogs, (R,RЈ)-4-methoxy-1-naphthylfenoterol (MNF), has a ␤ 2 -AR/␤ 1 -AR selectivity of 573 with an EC 50cAMP value of 3.90 nM.…”