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.