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.
MeSH terms
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3T3 Cells / drug effects
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3T3 Cells / metabolism
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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Adamantane / analogs & derivatives*
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Adamantane / pharmacology*
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Animals
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Cell Line / drug effects
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Dipeptides / pharmacology*
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Drug Resistance, Multiple*
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Fluoresceins / metabolism
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Humans
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Mice
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Narcotic Antagonists / pharmacology*
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Oligopeptides / pharmacology*
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Peptides, Cyclic / pharmacology
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Receptors, Opioid, delta / antagonists & inhibitors*
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Structure-Activity Relationship
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Tetrahydroisoquinolines*
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Transfection
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Verapamil / pharmacology
Substances
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2',6'-dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-alanine 1-adamantane amide
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2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl-alanyl tert-butyl amide
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2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carbonylamino-1-adamantane
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Dipeptides
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Fluoresceins
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N,N-diethyl-2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
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N,N-dimethyl-2',6'-dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl 1-adamantane amide
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N,N-dimethyl-2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl tert-butyl amide
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Narcotic Antagonists
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Oligopeptides
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Peptides, Cyclic
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Receptors, Opioid, delta
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Tetrahydroisoquinolines
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cyclo(2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)
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Verapamil
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Adamantane
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fluorexon