title: Opioids and efflux transporters. Part 4: influence of N-substitution on P-glycoprotein substrate activity of noroxymorphone analogues.
abstract: The efflux transporter protein P-glycoprotein (P-gp) is capable of affecting the central distribution of diverse neurotherapeutics, including opioid analgesics, through their active removal from the brain. P-gp located at the blood brain barrier has been implicated in the development of tolerance to opioids and demonstrated to be up-regulated in rats tolerant to morphine and oxycodone. We have previously examined the influence of hydrogen-bonding oxo-substitutents on the P-gp-mediated efflux of 4,5-epoxymorphinan analgesics, as well as that of N-substituted analogues of meperidine. Structure-activity relationships (SAR) governing N-substituent effects on opioid efficacy is well-established, however the influence of such structural modifications on P-gp-mediated efflux is unknown. Here, we present SAR describing P-gp recognition of a short series of N-modified 4,5-epoxymorphinans. Oxymorphone, naloxone, naltrexone, and nalmexone all failed to demonstrate P-gp substrate activity, indicating these opioid scaffolds contain structural features that preclude recognition by the transporter. These results are examined using mathematical molecular modeling and discussed in comparison to other opioid scaffolds bearing similar N-substituents.
authors.affiliation: Department of Pharmaceutical Sciences, MCPHS University, 19 Foster Street, Worcester, MA 01608, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Metcalf
authors.affiliation: Department of Pharmaceutical Sciences, Concordia University Wisconsin School of Pharmacy, 12800 North Lake Shore Drive, Mequon, WI 53097, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rosicky
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA.
authors.forename: Hazem E
authors.initials: HE
authors.lastname: Hassan
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA.
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Eddington
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
authors.affiliation: Department of Pharmaceutical Sciences, Concordia University Wisconsin School of Pharmacy, 12800 North Lake Shore Drive, Mequon, WI 53097, USA. Electronic address: chris.cunningham@cuw.edu.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cunningham
authors.affiliation: Department of Pharmaceutical Sciences, Lipscomb University College of Pharmacy and Health Sciences, One University Park Drive, Nashville, TN 37204, USA; Department of Pharmacology, Vanderbilt University School of Medicine, 23rd Avenue South, Nashville, TN 37232, USA. Electronic address: susan.mercer@lipscomb.edu.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mercer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009019:Morphinans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009019:Morphinans; C526569:noroxymorphone
keywords: Opioids; Oxymorphone; P-glycoprotein; Tolerance