Naloxone is a known potent mu receptor opioid antagonist used in the treatment of narcotic overdose. Two potential metabolites of naloxone in rats were proposed in 1976 which are formed by oxidation of the allyl side chain. Epoxidation of the allyl group was proposed to form Naloxone-(2,3-epoxide), that is an electrophilic naloxone metabolite that could be considered to be isosteric with the opioid antagonist naltrexone. Hydrolysis of Naloxone-(2,3-epoxide) provides the corresponding Naloxone -(2,3-dihydroxypropyl) metabolite. The choice of these metabolites for further study is based on the recognition that three- or four-carbon <i>N</i>-substituents impart essentially pure antagonist activity with relatively high opioid-binding site affinity, and preliminary studies in rats indicate that Naloxone-(2,3-epoxide) and Naloxone -(2,3-dihydroxypropyl) are active metabolites. These putative naloxone metabolites were synthesized and evaluated as reversing agents for opioid-induced respiratory depression. Binding studies indicated that the compounds bind to mu-opioid receptors, with a Ki of 30 nM for Naloxone-(2,3-epoxide). Preliminary in vivo studies in rats show promise for both Naloxone-(2,3-epoxide) and Naloxone -(2,3-dihydroxypropyl) as having potential for morphine induced respiratory depression reversal when dosed at 1 mg/kg in rats. In conclusion, Naloxone-(2,3-epoxide) is a potent mu-receptor antagonist with potential as an opioid overdose treatment option. The finding of an electrophilic metabolite of naloxone with opioid antagonistic activity provides a starting point for the discovery of long-acting agents for the treatment of substance abuse disorders.

Synthesis and biological characterization of an electrophilic naloxone metabolite with potent opioid antagonism activity

ACS Spring Meeting 2021

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