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Structural determinants of inhibitor interaction with the human organic cation transporter OCT2 (SLC22A2)

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Abstract

The organic cation transporter 2 (OCT2) provides an important pathway for the uptake of cationic compounds in the kidney, which is the essential step in their elimination from the organism. Although many drugs have been identified which interact with human OCT2, structural elements required for an interaction with OCT2 are not well defined. To address this issue, HEK293 cells stably expressing human OCT2 were generated. IC50 values of commonly used drugs for inhibition of [3H]MPP+ uptake were determined and correlated with physicochemical descriptors. We found only a significant correlation between the topological polar surface area (TPSA) and IC50 values (r = 0.71, p < 0.0001). Structural alignment of most potent inhibitor drugs of OCT2-mediated MPP+ uptake was used to construct a two-point pharmacophore consisting of an ion-pair interaction site and a hydrophobic aromatic site separated by 5.0 Å. Taken together, our data identify structural determinants for inhibitor interactions with OCT2.

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Acknowledgments

This work was supported by the Johannes und Frieda Marohn-Stiftung (JK, OZ), the Deutsche Forschungsgemeinschaft (Fr 1298/5-1), the Deutsche Krebshilfe (JK, grant 107854) and the Doktor Robert Pfleger-Stiftung (OZ). We thank Beate Endreß for providing expert technical assistance.

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  1. Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen–Nuremberg, Fahrstr. 17, 91054, Erlangen, Germany

    Oliver Zolk, Thomas F. Solbach, Jörg König & Martin F. Fromm

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  1. Oliver Zolk
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  2. Thomas F. Solbach
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  3. Jörg König
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  4. Martin F. Fromm
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Correspondence to Oliver Zolk.

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Zolk, O., Solbach, T.F., König, J. et al. Structural determinants of inhibitor interaction with the human organic cation transporter OCT2 (SLC22A2). Naunyn-Schmied Arch Pharmacol 379, 337–348 (2009). https://doi.org/10.1007/s00210-008-0369-5

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  • DOI: https://doi.org/10.1007/s00210-008-0369-5

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