Inhibition of human P-glycoprotein transport and substrate binding using a galantamine dimer

被引:28
作者
Namanja, Hilda A. [1 ]
Emmert, Dana [1 ]
Pires, Marcos M. [1 ]
Hrycyna, Christine A. [1 ]
Chmielewski, Jean [1 ]
机构
[1] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA
关键词
P-glycoprotein; Inhibition; Galantamine; Dimer; ATP Binding Cassette transporter; Blood-brain barrier; BLOOD-BRAIN-BARRIER; MULTIDRUG-RESISTANCE; ABC TRANSPORTERS; DRUG TRANSPORT; IN-VITRO; SITES; MICE; PENETRATION; VINBLASTINE; EXPRESSION;
D O I
10.1016/j.bbrc.2009.08.056
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 0.6 mu M. 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 0.3 to 1.6 mu M. 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. (C) 2009 Elsevier Inc. All rights reserved.
引用
收藏
页码:672 / 676
页数:5
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