title: Inhibition of human P-glycoprotein transport and substrate binding using a galantamine dimer.
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.
authors.affiliation: Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, USA.
authors.forename: Hilda A
authors.initials: HA
authors.lastname: Namanja
authors.forename: Dana
authors.initials: D
authors.lastname: Emmert
authors.forename: Marcos M
authors.initials: MM
authors.lastname: Pires
authors.forename: Christine A
authors.initials: CA
authors.lastname: Hrycyna
authors.forename: Jean
authors.initials: J
authors.lastname: Chmielewski
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D003630:Daunorubicin / Q000494:pharmacology; D019281:Dimerization; D004317:Doxorubicin / Q000494:pharmacology; D005702:Galantamine / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D005702:Galantamine; D004317:Doxorubicin; D014700:Verapamil; D003630:Daunorubicin
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