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

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Namanja HA, Emmert D, Pires MM, Hrycyna CA, Chmielewski J

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

Biochem Biophys Res Commun. 2009 Oct 30;388(4):672-6. doi: 10.1016/j.bbrc.2009.08.056. Epub 2009 Aug 14.

PubMed ID

19683513 [ View in PubMed

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Abstract

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 IC(50) value of approximately 0.6 microM. In addition, Gal-2 was found to inhibit the efflux of therapeutic substrates of P-gp, such as doxorubicin, daunomycin and verapamil with IC(50) values ranging from 0.3 to 1.6 microM. 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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Galantamine	P-glycoprotein 1	Protein	Humans	No	Inhibitor	Details