Inhibition of human P-glycoprotein transport and substrate binding using a galantamine dimer.
Inhibition of human P-glycoprotein transport and substrate binding using a galantamine dimer.
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DOI：
10.1016/j.bbrc.2009.08.056
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发表时间：
2009-10-30
影响因子：
3.1
通讯作者：
Chmielewski, Jean
中科院分区：
文献类型：
--
作者：
Namanja, Hilda A.;Emmert, Dana;Pires, Marcos M.;Hrycyna, Christine A.;Chmielewski, Jean
The human multidrug resistance transporter P-glycoprotein (P-gp) prevents the entry of compounds into the brain by an active efflux mechanism at the blood brain barrier (BBB). Treatment of neurodegenerative diseases, therefore, has become a challenge and the development of new reversible inhibitors of P-gp is pertinent to overcome this problem. We report the design and synthesis of a crosslinked agent based on the Alzheimer’s disease treatment galantamine (Gal-2) that inhibits P-gp-mediated efflux from cultured cells. Gal-2 was found to inhibit the efflux of the fluorescent P-gp substrate rhodamine 123 in cancer cells that over express P-gp with an IC50 value of approximately 0.8 µM. In addition, Gal-2 was found to inhibit the efflux of therapeutic substrates of P-gp, such as doxorubicin, daunomycin and verapamil with IC50 values ranging from 0.5 µM – 2 µM. Through competition experiments, it was determined that Gal-2 modulates P-gp mediated efflux by competing for the substrate binding sites. These findings support a potential role of agents, such as Gal-2, as inhibitors of P-gp at the BBB to augment treatment of neurodegenerative diseases.
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影响因子：
5.6
作者：
Lazarowski, Alberto;Czornyj, Liliana;D'Giano, Carlos
通讯作者：
D'Giano, Carlos
影响因子：
6.1
作者：
Boulton, DW;DeVane, CL;Markowitz, JS
通讯作者：
Markowitz, JS
影响因子：
2.9
作者：
Pires, Marcos M.;Hrycyna, Christine A.;Chmielewski, Jean
通讯作者：
Chmielewski, Jean
DOI：
10.1073/pnas.94.20.10594
发表时间：
1997-09-30
影响因子：
11.1
作者：
Dey, S;Ramachandra, M;Ambudkar, SV
通讯作者：
Ambudkar, SV
影响因子：
10.6
作者：
Uhr, M;Grauer, MT;Holsboer, F
通讯作者：
Holsboer, F