Agonistic activity of fentanyl analogs and their metabolites on opioid receptors.

PURPOSE

This study aims to expose the toxicity of fentanyl analogs and their metabolites by measuring the agonistic activity of these compounds on opioid receptors.

METHODS

The agonistic activity of fentanyl, four analogs of fentanyl (acetylfentanyl, butyrylfentanyl, tetrahydrofuranylfentanyl, and furanylfentanyl), and their metabolites were evaluated using a cell-based assay system, which measured the cellular cAMP level after the reaction of a test compound with cells expressing opioid receptor.

RESULTS

Fentanyl and its four analogs showed agonistic activity on μ-opioid receptor at < 10 nM, whereas these compounds were inactive at δ- and κ-opioid receptors even at 100 nM. Similarly, no metabolites showed agonistic activity on δ- and κ-opioid receptors. Meanwhile, several metabolites were active at μ-opioid receptor. β-Hydroxy metabolites exhibited strong activity nearly equivalent to those of the parent drugs. Some 4'-hydroxy metabolites and N-acyl group-hydroxylated metabolites were still active; however, their activity drastically decreased compared to the parent drugs.

CONCLUSIONS

Most of the metabolic reactions drastically diminish the agonistic activity of fentanyl analogs; exceptionally, β-hydroxylation maintains the activity at a level nearly equal to that of the parent drugs. However, β-hydroxy metabolites should contribute less to the poisoning caused by the ingestion of fentanyl analogs.