Towards reversal of transporter mediated drug efflux
Abstract
The treatment of central nervous system (CNS) diseases is challenged by the limited penetration of drug therapies in the brain. This lack of penetration is caused in part by P-glycoprotein (P-gp) at the blood-brain barrier that removes drugs from brain capillary endothelial cells before brain entry. Therefore, inhibiting the activity of P-gp at the blood-brain barrier (BBB) is attractive as a means to increase CNS drug penetration. We have examined two central nervous system disorder agents, olanzapine and venlafaxine, which do not penetrate the brain effectively because they are substrates of P-gp. We have synthesized a small library of bivalent agents based on the anti-depressant drug venlafaxine (effexor) and two homodimers of olanzapine. The homodimers show varying levels of inhibitory potency against P-gp in a multidrug resistant MCF7-DX1 breast cancer cell line.
Degree
M.S.
Advisors
Chmielewski, Purdue University.
Subject Area
Pharmacology|Biochemistry|Organic chemistry
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