title: Nanoconjugated NAP as a Potent and Periphery Selective Mu Opioid Receptor Modulator To Treat Opioid-Induced Constipation.
abstract: Opioids are the mainstay for cancer and noncancer pain management. However, their use is often associated with multiple adverse effects. Among them, the most common and persistent one is probably opioid-induced constipation (OIC). Periphery selective opioid antagonists may alleviate the symptoms of OIC without compromising the analgesic effects of opioids. Recently our laboratories have identified one novel lead compound, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)acetamido]morphinan (NAP), as a peripherally selective mu opioid receptor ligand carrying subnanomolar affinity to the mu opioid receptor and over 100-folds of selectivity over both the delta and kappa opioid receptors, with reasonable oral availability and half-life, and potential to treat OIC. Nanoparticle-based drug delivery systems are now widely considered due to their technological advantages such as good stability, high carrier capacity, low therapeutic side effects, etc. Herein we report nanoparticle supported NAP as a potential candidate for OIC treatment with improved peripheral selectivity over the original lead compound NAP.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University , 800 E Leigh Street, Richmond, Virginia 23298, United States.
authors.forename: Guoyan G
authors.initials: GG
authors.lastname: Xu
authors.affiliation: Department of Chemical and Life Science Engineering, Virginia Commonwealth University , 401 West Main Street, Richmond, Virginia 23284, United States.
authors.forename: Olga Yu
authors.initials: OY
authors.lastname: Zolotarskaya
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E Leigh Street, Richmond, Virginia 23298, United States; Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States.
authors.forename: Dwight A
authors.initials: DA
authors.lastname: Williams
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University , 800 E Leigh Street, Richmond, Virginia 23298, United States.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
authors.forename: Hamid I
authors.initials: HI
authors.lastname: Akbarali
authors.affiliation: Department of Chemical and Life Science Engineering, Virginia Commonwealth University, 401 West Main Street, Richmond, Virginia 23284, United States; Department of Pharmaceutics, Virginia Commonwealth University, 410 N 12th Street, Richmond, Virginia 23298, United States; Massey Cancer Center, Virginia Commonwealth University, 401 College Street, Richmond, Virginia 23298, United States.
authors.forename: Hu
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E Leigh Street, Richmond, Virginia 23298, United States; Massey Cancer Center, Virginia Commonwealth University, 401 College Street, Richmond, Virginia 23298, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
keywords: Mu opioid receptor antagonist; NAP; Opioid-induced constipation; Periphery selective; nanoconjugate