Structure-Activity Relationship Studies on 6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

A series of derivatives were synthesized and studied with the aim to investigate the structure–activity relationships of the two P-glycoprotein(P-gp) modulators elacridar and tariquidar. Then, different aryl-substituted amides were inserted, and to explore the effects of varying the amide function, the corre- sponding isosteric ester derivatives and some alkylamine ana- logues were synthesized. The new compounds were studied to evaluatetheir P-gp interaction profile and selectivity toward the two other ABC transporters, multidrug-resistance-associat- ed protein-1(MRP-1)and breast cancer resistance protein (BCRP).Investigation of the chemical stability of the amide and ester derivatives toward spontaneous or enzymatic hydrolysis showed that these compounds were stable in phosphate-buf- fered saline and human plasma. This study allowed us to eval- uate the selectivity of the three series on the three efflux pumps and to propose the structural requirements that define the P-gp interaction profile. We identified two P-gp substrates, a P-gp inhibitor, and three ester derivatives that were active on BCRP, which opens anew scenario in the development of li- gands active toward this pump.