title: 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.
authors.affiliation: Peptide Neurochemistry Group, LCBRA, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709, USA.
authors.forename: T
authors.initials: T
authors.lastname: Lovekamp
authors.forename: P S
authors.initials: PS
authors.lastname: Cooper
authors.forename: J
authors.initials: J
authors.lastname: Hardison
authors.forename: S D
authors.initials: SD
authors.lastname: Bryant
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.forename: G
authors.initials: G
authors.lastname: Balboni
authors.forename: S
authors.initials: S
authors.lastname: Salvadori
authors.forename: L H
authors.initials: LH
authors.lastname: Lazarus
mesh_terms: D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines; D014162:Transfection; D014700:Verapamil / Q000494:pharmacology
chemical_list: C402272:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-alanine 1-adamantane amide; C434931:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl-alanyl tert-butyl amide; C434929:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carbonylamino-1-adamantane; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004151:Dipeptides; D005452:Fluoresceins; C434928:N,N-diethyl-2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; C402273:N,N-dimethyl-2',6'-dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl 1-adamantane amide; C434930:N,N-dimethyl-2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl tert-butyl amide; D009292:Narcotic Antagonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta; D044005:Tetrahydroisoquinolines; C434932:cyclo(2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl); D014700:Verapamil; D000218:Adamantane; C007740:fluorexon