Essential features of the P-glycoprotein pharmacophore as defined by a series of reserpine analogs that modulate multidrug resistance.

Pearce, Homer L.; Safa, Ahmad R.; Bach, Nicholas J.; Winter, Mark A.; Cirtain, Margaret C.; Beck, William T.

doi:10.1073/pnas.86.13.5128

Cited by 210 publications

(117 citation statements)

References 11 publications

(12 reference statements)

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“…Since various anthracycline analogs (Friche et al, 1990a) and VCR (Inaba & Nagashima, 1986) ['251]iodomycin in EHR2/DNR + relative to EHR2 (42 and 207 fmol 10-6 cells, respectively), in agreement with the data of Busche et al, (1989a) indicating that iodomycin itself is transported by the MDR efflux process. Zamora et al, 1988 andPearce et al, 1989 have shown that some ideal structures have to be present to fulfill the demands for a good modulator: at least two planar aromatic rings, a basic nitrogen that would be positively charged at physiological pH and some lipophilicity. The tested anthracycline analogs fulfill all these demands and yet their effects as modulators are very varying.…”

Section: Discussionmentioning

confidence: 99%

Effect of anthracycline analogs on photolabelling of p-glycoprotein by [125I]iodomycin and [3H]azidopine: relation to lipophilicity and inhibition of daunorubicin transport in multidrug resistant cells

Friche

Demant²,

Sehested³

et al. 1993

Br J Cancer

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Section: Discussionmentioning

confidence: 99%

Effect of anthracycline analogs on photolabelling of p-glycoprotein by [125I]iodomycin and [3H]azidopine: relation to lipophilicity and inhibition of daunorubicin transport in multidrug resistant cells

Friche

Demant²,

Sehested³

et al. 1993

Br J Cancer

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“…While relative lipophilicity, the presence of a basic nitrogen atom and molecular refractivity have been suggested to be important factors for efficient interaction of an MDR reversing agent with Pglycoprotein [154,155], the structural determinants or pharmacophore of chemically and pharmacologically diverse MDR modulators remain largely unknown. However, several reports have further defined important features of P-glycoprotein pharmacophore [156][157][158][159][160][161][162][163][164][165][166].…”

Section: Specific Inhibitorsmentioning

confidence: 99%

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

Safa

2004

CMCACA

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A major problem in cancer treatment is the development of resistance to multiple chemotherapeutic agents in tumor cells. A major mechanism of this multidrug resistance (MDR) is overexpression of the MDR1 product P-glycoprotein, known to bind to and transport a wide variety of agents. This review concentrates on the progress made toward understanding the role of this protein in MDR, identifying and characterizing the drug binding sites of P-glycoprotein, and modulating MDR by P-glycoprotein-specific inhibitors. Since our initial discovery that Pglycoprotein binds to vinblastine photoaffinity analogs, many P-glycoprotein-specific photoaffinity analogs have been developed and used to identify the particular domains of Pglycoprotein capable of interacting with these analogs and other P-glycoprotein substrates. Furthermore, significant advances have been made in delineating the drug binding sites of this protein by studying mutant P-glycoprotein. Photoaffinity labeling experiments and the use of sitedirected antibodies to several domains of this protein have allowed the localization of the general binding domains of some of the cytotoxic agents and MDR modulators on P-glycoprotein. Moreover, site-directed mutagenesis studies have identified the amino acids critical for the binding of some of these agents to P-glycoprotein. Furthermore, equilibrium binding assays using plasma membranes from MDR cells and radioactive drugs have aided our understanding of the modes of drug interactions with P-glycoprotein. Based on the available data, a topological model of Pglycoprotein and the approximate locations of its drug binding sites, as well as a proposed classification of multiple drug binding sites of this protein, is presented in this review.

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“…These include a basic nitrogen atom, and the presence of at least one planar aromatic ring (Pearce et al, 1989). The β-ligands tested are all weak bases, and therefore positively charged at physiological pH (pKa ≈ 9.5).…”

Section: Whereas Both Therapeutic Classes Inhibit Rh123 Efflux With Imentioning

confidence: 99%

Modulation of P-glycoprotein activity in Calu-3 cells using steroids and β-ligands

Hamilton

Yazdanian

Audus

2001

International Journal of Pharmaceutics

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Essential features of the P-glycoprotein pharmacophore as defined by a series of reserpine analogs that modulate multidrug resistance.

Abstract: We have shown previously that reserpine is an effective "modulator" of P-glycoprotein-associated multidrug resistance (MDR). In addition to enhancing drug cytotoxicity in our multidrug-reistant human leukemia cell line,

Cited by 210 publications

References 11 publications

Effect of anthracycline analogs on photolabelling of p-glycoprotein by [125I]iodomycin and [3H]azidopine: relation to lipophilicity and inhibition of daunorubicin transport in multidrug resistant cells

Effect of anthracycline analogs on photolabelling of p-glycoprotein by [125I]iodomycin and [3H]azidopine: relation to lipophilicity and inhibition of daunorubicin transport in multidrug resistant cells

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

Modulation of P-glycoprotein activity in Calu-3 cells using steroids and β-ligands

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