title: Human plasma-mediated hypoxic activation of indolequinone-based naloxone pro-drugs.
abstract: Hypoxia is known to occur in tissues in response to narcotic analgesic therapy using as a result of respiratory depression. The aim of this study was to synthesize a narcotic antagonist pro-drug that can be activated by tissue hypoxia to prevent the damage associated with respiratory depression. We synthesized three different pro-drugs of the narcotic antagonist naloxone utilizing indolequinone as the hypoxia-sensitive moiety. The indolequinone structure in the pro-drugs was designed to have an open reactive point at the N-1 position offering the possibility of further conjugation with macromolecules to modify the bio-availability of these pro-drugs in vivo. A pro-drug (labeled 1) where naloxone and the indolequinone moiety were linked through a carbonate bond was rapidly hydrolyzed in phosphate buffered saline. However, two additional pro-drugs (labeled 2 and 3) having carbamate linkers were stable in phosphate buffered saline for 24h. The reductive release of naloxone from the pro-drugs was achieved in the presence of the bio-reductive enzyme DT-Diaphorase, with about 80% release occurring from the two pro-drugs in 24h. More than 99% of naloxone was released from pro-drug 2 in 30% human plasma, however the release only occurred under hypoxic conditions. This system provides a potential means for feedback control to counter critical respiratory depression induced by narcotic analgesics.
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Baohua
authors.initials: B
authors.lastname: Huang
authors.forename: Shengzhuang
authors.initials: S
authors.lastname: Tang
authors.forename: Ankur
authors.initials: A
authors.lastname: Desai
authors.forename: Xue-min
authors.initials: XM
authors.lastname: Cheng
authors.forename: Alina
authors.initials: A
authors.lastname: Kotlyar
authors.forename: Abraham
authors.initials: A
authors.lastname: Van Der Spek
authors.forename: Thommey P
authors.initials: TP
authors.lastname: Thomas
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
mesh_terms: D001773:Blood Cells / Q000187:drug effects; D015687:Cell Hypoxia; D006801:Humans; D045563:Indolequinones / Q000737:chemistry*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009270:Naloxone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D045563:Indolequinones; D009292:Narcotic Antagonists; D011355:Prodrugs; D009270:Naloxone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human