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: Baohua Huang, Shengzhuang Tang, Ankur Desai, Xue-min Cheng, Alina Kotlyar, Abraham Van Der Spek, Thommey P Thomas, James R Baker Jr
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 17 Pg. 5016-20 (Sep 01 2009) ISSN: 1464-3405 [Electronic] England
• PMID: 19632838 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Indolequinones
• Narcotic Antagonists
• Prodrugs
• Naloxone
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human

Topics

• Blood Cells (drug effects)
• Cell Hypoxia
• Humans
• Indolequinones (chemistry)
• NAD(P)H Dehydrogenase (Quinone) (metabolism)
• Naloxone (analogs & derivatives, chemical synthesis, pharmacology)
• Narcotic Antagonists (chemical synthesis, chemistry, pharmacology)
• Prodrugs (chemical synthesis, chemistry, pharmacology)