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.
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Authors | T Lovekamp, P S Cooper, J Hardison, S D Bryant, R Guerrini, G Balboni, S Salvadori, L H Lazarus |
Journal | Brain research
(Brain Res)
Vol. 902
Issue 1
Pg. 131-4
(May 25 2001)
ISSN: 0006-8993 [Print] Netherlands |
PMID | 11376603
(Publication Type: Comparative Study, Journal Article)
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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
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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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