Allosteric modifiers of neuronal nicotinic acetylcholine receptors: new methods, new opportunities
Med Res Rev. 2007 Sep;27(5):723-53
Moaddel R, Jozwiak K, Wainer IW
Allosteric, non-competitive inhibitors (NCIs) of neuronal nicotinic acetylcholine receptors (nAChRs) have been shown to produce a wide variety of clinically relevant responses. Many of the observed effects are desired as the nAChR is the therapeutic target, while others are undesired consequences due to off-target binding at the nAChR. Thus, the determination of whether or not a lead drug candidate is an NCI should play an important role in drug discovery programs. However, the current experimental techniques used to identify NCIs are challenging, expensive, and time consuming. This review focuses on an alternative approach to the investigation of interactions between test compounds and nAChRs based upon liquid chromatographic stationary phases containing cellular fragments from cell lines expressing nAChRs. The development and validation of these phases as well as their use in drug discovery and pharmacophore modeling are discussed.
Comparative molecular field analysis of the binding of the stereoisomers of fenoterol and fenoterol derivatives to the beta2 adrenergic receptor
J Med Chem. 2007 Jun 14;50(12):2903-15. Epub 2007 May 17
Jozwiak K, Khalid C, Tanga MJ, Berzetei-Gurske I, Jimenez L, Kozocas JA, Woo A, Zhu W, Xiao RP, Abernethy DR, Wainer IW
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.
Interaction of noncompetitive inhibitors with the alpha3beta2 nicotinic acetylcholine receptor investigated by affinity chromatography and molecular docking
J Med Chem. 2007 Nov 29;50(24):6279-83. Epub 2007 Oct 31
Jozwiak K, Ravichandran S, Collins JR, Moaddel R, Wainer IW
A molecular model of the alpha3beta2 nAChR lumen channel was constructed and hydrophobic clefts were observed near the receptor gate. Docking simulations indicated that ligand-nAChR complexes were formed by hydrophobic interactions with the cleft and hydrogen bond interactions. The equilibrium constants and association and dissociation constant rates associated with the binding interactions were determined using nonlinear chromatography on an immobilized alpha3beta2 nAChR column. The computational-chromatography approach can be used to predict and describe ligand-nAChR interactions.