Received for publication October 19, 2006.
Revised March 12, 2007.
Accepted for publication March 14, 2007.

Structure-Activity Relationships for Interaction with Multidrug Resistance Protein 2 (ABCC2/MRP2): The Role of Torsion Angle for a Series of Biphenyl-Substituted Heterocycles

Abstract

Multidrug resistance protein 2 (ABCC2/MRP2) is an ATP-binding cassette transporter involved in the absorption, distribution and excretion of drugs and xenobiotics. Identifying compounds that are ABCC2/MRP2 substrates and/or inhibitors and understanding their structure-activity-relationships (SAR) are important considerations in the selection and optimization of drug candidates. In the present study, the interactions between ABCC2/MRP2 and a series of biphenyl-substituted heterocycles were evaluated using Caco-2 cells and human ABCC2/MRP2 gene transfected MDCK cells. It was observed that ABCC2/MRP2 transport and/or inhibition profile, both in nature and in magnitude, depends strongly on the substitution patterns of the biphenyl system. In particular, different ortho-substitutions cause various degrees of twisting between the two-phenyl rings, resulting in changing interactions between the ligands and ABCC2/MRP2. The compounds with small ortho functions (hydrogen, fluorine and oxygen), thus displaying the smallest torsion angles of biphenyl (37^o - 45^o), are neither substrates nor inhibitors of human ABCC2/MRP2. The transporter interactions increase as the steric bulkness of the ortho-substitutions increase. When the tested compounds are 2-methyl substituted biphenyls, they exhibit moderate torsion angles (54^o -65^o) and behave as ABCC2/MRP2 substrates as well as mild inhibitors (10-40% compared to MK571). For the 2, 2'-dimethyl substituted biphenyls, the torsions are enhanced (78^o - 87^o), and so are the inhibition of ABCC2/MRP2. This class of compounds behaves as strong inhibitors of ABCC2/MRP2. These results can be used to define the three-dimensional structural requirements of ABCC2/MRP2 interaction with their substrates and inhibitors, as well as provide SAR guidance to support drug discovery.

Key words: ABC transporters, drug transport, inhibition, MRP, structure-activity relationships, transporters

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