Lack of drug penetration through the blood-brain barrier (BBB) represents a formidable hurdle to treatment of central nervous system (CNS) diseases and the development of CNS drugs. A significant amount of BBB penetration is blocked by an efflux transporter called the human multiple drug resistance 1 (MDR1) transporter. This transporter effluxes a wide range of chemically and structurally diverse compounds from epithelial cells within the BBB to the blood stream by ATP hydrolysis at nucleotide binding domains (NBDs) and conformational changes. Diphenylpropylamine derivatives, morphine alkaloids and triptans represent three chemical classes of CNS agonists that show large differences in their MDR1 efflux rates and transport properties within a chemical class, despite the similarities in their molecular structures. Although there have been numerous studies, the relationship between the agonist's molecular structure and transport rates remains to be clarified. The proposed work will test the central hypothesis that the agonist MDR1 transport rate is controlled by drug binding near the extracellular side (blood-side) of the membrane (near Y953) and without direct interaction with the NBDs. The proposal was divided into two specific aims: 1) to characterize the interaction of agonists with human MDR1, to determine their effect on ATP hydrolysis and to establish their transport rates with MDCK cells overexpressing human MDR1 and 2) to locate the agonist binding sites on human MDR1. Innovative NMR and computational methods will be used to explore the interaction between agonists and human MDR1. These technologies will open the door to screening a wide range of therapeutics with human MDR1. Understanding the relationship between molecular structure and transport rates will also fill significant gaps in our understanding of the transporter as wellas lead to novel neurotherapeutics, acceleration of CNS drug development and improvements in the effectiveness of current CNS drugs.

Public Health Relevance

According to the NINDS and NIMH, neurological disorders and serious mental illness afflict upwards of 25% of the U.S. population (i.e. 60 million people). Development of new and novel CNS drugs are essential to the treatment of this population, but are blocked by poor brain penetration by the multiple drug resistance (MDR) transporter. The proposed studies on MDR transporter will lead to new and innovative technologies that will accelerate CNS drug development and improve the efficacy of current treatments.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1)
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Chin, Jean
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University of Georgia
Schools of Pharmacy
United States
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Roberts, Arthur G; Gibbs, Morgan E (2018) Mechanisms and the clinical relevance of complex drug-drug interactions. Clin Pharmacol 10:123-134
Gibbs, Morgan E; Wilt, Laura A; Ledwitch, Kaitlyn V et al. (2018) A Conformationally Gated Model of Methadone and Loperamide Transport by P-Glycoprotein. J Pharm Sci 107:1937-1947
Wilt, Laura A; Nguyen, Diana; Roberts, Arthur G (2017) Insights Into the Molecular Mechanism of Triptan Transport by P-glycoprotein. J Pharm Sci 106:1670-1679
Ledwitch, Kaitlyn V; Roberts, Arthur G (2017) Cardiovascular Ion Channel Inhibitor Drug-Drug Interactions with P-glycoprotein. AAPS J 19:409-420
Ledwitch, Kaitlyn V; Gibbs, Morgan E; Barnes, Robert W et al. (2016) Cooperativity between verapamil and ATP bound to the efflux transporter P-glycoprotein. Biochem Pharmacol 118:96-108
Ledwitch, Kaitlyn V; Barnes, Robert W; Roberts, Arthur G (2016) Unravelling the complex drug-drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein. Biosci Rep 36: