title: Opioids and efflux transporters. Part 3: P-glycoprotein substrate activity of 3-hydroxyl addition to meperidine analogs.
abstract: Numerous studies have shown that many clinically employed opioid analgesics are substrates for P-glycoprotein (P-gp), suggesting that up-regulation of P-gp may contribute to the development of central tolerance to opioids. The studies herein focus on the development of SAR for P-gp substrate activity in the meperidine series of opioids. Addition of a 3-OH to meperidine and the ketone analog of meperidine yielding bemidone and ketobemidone, respectively, significantly increased P-gp substrate affinity. The results of this study have implications in the development of novel analgesics to be utilized as tools to study the contribution of P-gp on the development of central tolerance to opioids.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Room 543, Baltimore, MD 21201, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mercer
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cunningham
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Eddington
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D017665:Hydroxyl Radical / Q000737:chemistry*; D008614:Meperidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011957:Receptors, Opioid / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D011957:Receptors, Opioid; D017665:Hydroxyl Radical; D008614:Meperidine; C012394:ketobemidone; C530875:bemidone