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Bioorg Med Chem ; 16(22): 9745-56, 2008 Nov 15.
Article in English | MEDLINE | ID: mdl-18849167

ABSTRACT

A series of chalcogenopyrylium dyes were evaluated as modulators/inhibitors of P-glycoprotein (Pgp). Their ability to inhibit verapamil (VER)-dependent ATPase activity (IC(50) values) in lipid-activated, mouse Cys-less mdr3 Pgp was determined. Their ability to promote calcein-AM (CAM) uptake in MDCKII-MDR1 cells and their capacity to be transported by Pgp in monolayers of MDCKII-MDR1 cells were also evaluated. The chalcogenopyrylium dyes promoted CAM uptake with values of EC(50) between 5 x 10(-6) and 3.5 x 10(-5)M and 7 of the 9 dyes examined in transport studies were substrates for Pgp with efflux ratios (P(BA/AB)) between 14 and 390. Binding of three compounds (1-S, 3-S, and 4-S) to Pgp was also assessed by fluorescence. These three thiopyrylium dyes showed increased fluorescence upon binding to Pgp, giving apparent binding constants, K(app), on the order of 10(-7) to 10(-6)M. Compound 8-Te was particularly intriguing since it appeared to influence Pgp at low micromolar concentrations as evidenced by its influence on VER-stimulated ATPase activity (IC(50) of 1.2 x 10(-6)M), CAM uptake (EC(50) of 5.4 x 10(-6)M), as well as [(3)H]-vinblastine transport by Pgp in cells (IC(50) of 4.3 x 10(-6)M) and within inside-out membrane vesicles (IC(50) of 9.6 x 10(-6)M). Yet, Pgp did not influence the distribution of 8-Te in MDCKII-MDR1 monolayers suggesting that 8-Te may bind to an allosteric site.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Chalcogens/chemistry , Fluorescent Dyes/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adenosine Triphosphatases/metabolism , Animals , Biological Transport , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Cell Membrane Permeability/drug effects , Cell Polarity , Cells, Cultured , Dogs , Drug Resistance, Multiple , Fluoresceins/chemistry , Fluoresceins/metabolism , Fluorescent Dyes/chemistry , Fluorescent Dyes/metabolism , Humans , Inhibitory Concentration 50 , Verapamil/chemical synthesis , Verapamil/chemistry , Verapamil/pharmacology
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