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Thedevelopment of P-glycoprotein (P-gp) ligands remains of considerableinterest, mostly for investigating the protein’s structureand transport mechanism. In recent years, many different generationsof ligands have been tested for their ability to modulate P-gp activity.The aim of the present work is to perform SAR studies on tetrahydroisoquinolinederivatives in order to design potent and selective P-gp ligands.For this purpose, the effect of bioisosteric replacement and the roleof flexibility have been investigated, and four series of tetrahydroisoquinolineligands have been developed: (a) 2-aryloxazole bioisosteres, (b) elongatedanalogues, (c) 2H-chromene, and (d) 2-biphenyl derivatives.The results showed that both 2-biphenyl derivative 20band elongated derivative 6gbehaved as strong P-gpsubstrates. In conclusion, important aspects for developing potentand selective P-gp ligands have been highlighted, providing a solidstarting point for further optimization. [ABSTRACT FROM AUTHOR]