Kanamori Tatsuyuki, Okada Yuki, Segawa Hiroki, Yamamuro Tadashi, Kuwayama Kenji, Tsujikawa Kenji, Iwata Yuko T
National Research Institute of Police Science, 6-3-1, Kashiwanoha, Kashiwa, Chiba, 277-0882, Japan.
Forensic Toxicol. 2022 Jan;40(1):156-162. doi: 10.1007/s11419-021-00602-w. Epub 2021 Nov 13.
This study aims to expose the toxicity of fentanyl analogs and their metabolites by measuring the agonistic activity of these compounds on opioid receptors.
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.
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.
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.
本研究旨在通过测量这些化合物对阿片受体的激动活性来揭示芬太尼类似物及其代谢物的毒性。
使用基于细胞的检测系统评估芬太尼、四种芬太尼类似物（乙酰芬太尼、丁酰芬太尼、四氢呋喃基芬太尼和呋喃基芬太尼）及其代谢物的激动活性，该系统在测试化合物与表达阿片受体的细胞反应后测量细胞内cAMP水平。
芬太尼及其四种类似物在<10 nM时对μ-阿片受体表现出激动活性，而这些化合物即使在100 nM时对δ-和κ-阿片受体也无活性。同样，没有代谢物对δ-和κ-阿片受体表现出激动活性。同时，几种代谢物在μ-阿片受体上具有活性。β-羟基代谢物表现出与母体药物几乎相当的强活性。一些4'-羟基代谢物和N-酰基羟基化代谢物仍然具有活性；然而，与母体药物相比，它们的活性大幅下降。
大多数代谢反应会大幅降低芬太尼类似物的激动活性；例外的是，β-羟基化使活性维持在与母体药物几乎相等的水平。然而，β-羟基代谢物对摄入芬太尼类似物引起的中毒贡献应较小。
