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

Brain Res. 2001 May 25;902(1):131-4. doi: 10.1016/s0006-8993(01)02363-0.

Abstract

Analogues Dmt-Tic (2',6'-dimethyl-L-tyrosine-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) pharmacophore, a potent delta-opioid receptor antagonist, inhibited hMDR1 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(Et)2-Dmt-Tic-OH, H-Dmt-Tic-Ala-NH-tert-butyl amide and cyclo(Dmt-Tic). 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.

Publication types

  • Comparative Study

MeSH terms

  • 3T3 Cells / drug effects
  • 3T3 Cells / metabolism
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • Adamantane / analogs & derivatives*
  • Adamantane / pharmacology*
  • Animals
  • Cell Line / drug effects
  • Dipeptides / pharmacology*
  • Drug Resistance, Multiple*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fluoresceins / metabolism
  • Humans
  • Mice
  • Narcotic Antagonists / pharmacology*
  • Oligopeptides / pharmacology*
  • Peptides, Cyclic / pharmacology
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines*
  • Transfection
  • Verapamil / pharmacology

Substances

  • 2',6'-dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-alanine 1-adamantane amide
  • 2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl-alanyl tert-butyl amide
  • 2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carbonylamino-1-adamantane
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Dipeptides
  • Fluoresceins
  • N,N-diethyl-2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
  • N,N-dimethyl-2',6'-dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl 1-adamantane amide
  • N,N-dimethyl-2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl tert-butyl amide
  • Narcotic Antagonists
  • Oligopeptides
  • Peptides, Cyclic
  • Receptors, Opioid, delta
  • Tetrahydroisoquinolines
  • cyclo(2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)
  • Verapamil
  • Adamantane
  • fluorexon