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

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.
AuthorsT Lovekamp, P S Cooper, J Hardison, S D Bryant, R Guerrini, G Balboni, S Salvadori, L H Lazarus
JournalBrain research (Brain Res) Vol. 902 Issue 1 Pg. 131-4 (May 25 2001) ISSN: 0006-8993 [Print] Netherlands
PMID11376603 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • 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
Topics
  • 3T3 Cells (drug effects, metabolism)
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors)
  • Adamantane (analogs & derivatives, pharmacology)
  • Animals
  • Cell Line (drug effects)
  • Dipeptides (pharmacology)
  • Drug Resistance, Multiple
  • Fibroblasts (drug effects, 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)

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