Caged Naloxone Synthesis, characterization, and stability of 3-O-(4,5-Dimethoxy-2-nitrophenyl)carboxymethyl Naloxone (CNV-NLX)

The photolabile analogue of the broad-spectrum opioid antagonist naloxone, 3-O-(4,5-dimethoxy-2-nitrophenyl)carboxymethyl naloxone (also referred to as "caged naloxone", 3-O-(alpha-carboxy-6-nitroveratryl)naloxone, CNV-NLX), has been found to be a valuable biochemical probe. While the synthesis of CNV-NLX is simple, its characterization is complicated by the fact that it is produced as a mixture of alpha R,5R,9R,13S,14S and alpha S,5R,9R,13S,14S diastereomers. Using long-range and heteronuclear NMR correlations, the H-1 NMR and C-13 NMR resonances of both diastereomers have been fully assigned, confirming the structures. Monitoring of solutions of CNV-NLX in saline buffer, in methanol, and in DMSO has shown CNV-NLX to be stable for over a week under fluorescent laboratory lights at room temperature. Exposure of such solutions to lambda 365 nm from a hand-held UV lamp led to the formation of naloxone and CNV-related breakdown products.

Lewin, A. H., Fix, S. E., Zhong, D., Mayer, L. D., Burgess, J. P., Mascarella, S. W., ... Carroll, F. I. (2018). Caged Naloxone: Synthesis, characterization, and stability of 3-O-(4,5-Dimethoxy-2-nitrophenyl)carboxymethyl Naloxone (CNV-NLX). ACS Chemical Neuroscience, 9(3), 563-577. DOI: 10.1021/acschemneuro.7b00378