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 (SARs) 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 Madin-Darby canine kidney 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) and, thus, the ones displaying the smallest torsion angles of biphenyl (37-45°) are neither substrates nor inhibitors of human ABCC2/MRP2. The transporter interactions increase as the steric bulkiness of the ortho-substitutions increase. When the tested compounds are 2-methyl substituted biphenyls, they exhibit moderate torsion angles (54-65°) and behave as ABCC2/MRP2 substrates as well as mild inhibitors [10-40% compared with 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethyl-sulfanyl)methylsulfanyl] propionic acid (MK571)]. For the 2,2′-dimethyl substituted biphenyls, the torsions are enhanced (78-87°) and so is 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 to provide SAR guidance to support drug discovery.
Footnotes
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doi:10.1124/dmd.106.013250.
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ABBREVIATIONS: MCP, multidrug resistance-associated protein; ABC, ATP-binding cassette; ABCC2/MRP2, multidrug resistance protein 2; SAR, structure-activity relationship; GSH, glutathione; GST, glutathione S-transferase; Caco-2, human colon carcinoma cell; MDCK, Madin-Darby canine kidney; FBS, fetal bovine serum; HBSS, Hanks' balanced salt solution; MK571, [3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethyl-carbamoylethylsulfanyl)methylsulfanyl] propionic acid]; calcein-AM, calcein acetoxymethyl ester; MS, mass spectrometry; P-gp, P-glycoprotein; ClogP, ClogP; tPSA, topological polar surface area; LogD, distribution coefficient; HPLC, high-performance liquid chromatography; CoMFA, comparative molecular field analysis; IUPAC, International Union of Pure and Applied Chemistry.
- Received October 10, 2006.
- Accepted March 14, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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