Inhibition of human multidrug resistance P-glycoprotein 1 by analogues of a potent δ-opioid antagonist

Analogues Dmt-Tic (2 ' ,6 ' -dimlthyl-L-tyrosine-1,2,3,3-tetrahydroisquinoline-3-carboxylic acid) pharmacophore. a potent delta -opioid receptor antagonist, inhibited hMDRI P-GP expressed in a G-185 fibroblast cell line in a manner similar to verapamil. N,N(Me)(2)-Dmt-Tic-NH-1 -adamantane. H-Dmt-Tic-NH-1-adamantane, H-Dmt-Tic-Ala-NH-1-adamantane and N,N(Me)(2)-Dmt-Tic-NH-tBut were highly effective inhibitors. Weaker inhibition was observed with N,N(Er)(2)-Dmt-Tic-OH, H-Dmt-Tic-Ala-NH-tert-butyl amide and cyclo(Dmt- Tie). Results demonstrate that N- and C-terminal hydrophobic /lipophilic analogues of the Dmt-Tic pharmacophore inhibit hMDR1 and point to a potential role as chemosensitizing agents in chemotherapy for cancers containing hMDR1. (C) 2001 Published by Elsevier Science B.V.