PT  - JOURNAL ARTICLE
AU  - Yurong Lai
AU  - Li Xing
AU  - Gennadiy I. Poda
AU  - Yiding Hu
TI  - Structure-Activity Relationships for Interaction with Multidrug Resistance Protein 2 (ABCC2/MRP2): The Role of Torsion Angle for a Series of Biphenyl-Substituted Heterocycles
AID  - 10.1124/dmd.106.013250
DP  - 2007 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 937--945
VI  - 35
IP  - 6
4099  - http://dmd.aspetjournals.org/content/35/6/937.short
4100  - http://dmd.aspetjournals.org/content/35/6/937.full
SO  - Drug Metab Dispos2007 Jun 01; 35
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics