title: Qualitative assessment of IC50 values of inhibitors of the neuronal nicotinic acetylcholine receptor using a single chromatographic experiment and multivariate cluster analysis.
abstract: It has been widely demonstrated that affinity chromatography can be used to derive binding affinities, and that these affinities can be correlated to data obtained using standard techniques such as membrane binding, ultrafiltration and equilibrium dialysis. The purpose of this study is to evaluate the use of immobilized nicotinic acetylcholine receptor stationary phase in chromatographic experiments to assess the functional activity of series of noncompetitive inhibitors (NCIs) as reflected in their IC50 values. Chromatographically determined retention values and computer generated molecular descriptors were obtained for 29 compounds and the data were analyzed by cluster analysis. The approach qualitatively ranked the test compounds as efficient NCIs (low IC50 values) or poor NCIs (high IC50 values). The data obtained with the 29 compounds used in this study demonstrate that the experimental approach had been able to place 25 of these compounds in the correct IC(50) clusters. To our knowledge, this is the first relationship established between chromatographic retention and IC50 for membrane-bound receptors. These results suggest that the chromatographic approach may be useful in development of lead drug candidates including the determination of off-target binding.
authors.affiliation: Gerontology Research Center, National institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. krzysztof.jozwiak@am.lublin.pl
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.forename: Rika
authors.initials: R
authors.lastname: Yamaguchi
authors.forename: Sarangan
authors.initials: S
authors.lastname: Ravichandran
authors.forename: Jack R
authors.initials: JR
authors.lastname: Collins
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D002846:Chromatography, Affinity / Q000379:methods*; D016000:Cluster Analysis; D020128:Inhibitory Concentration 50; D015999:Multivariate Analysis; D018733:Nicotinic Antagonists / Q000032:analysis* / Q000494:pharmacology*; D011978:Receptors, Nicotinic; D013816:Thermodynamics
chemical_list: D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic