2,5-Dimethoxyamphetamine-derived designer drugs: Studies on the identification of cytochrome P450 (CYP) isoenzymes involved in formation of their main metabolites and on their capability to inhibit CYP2D6

Abstract

The designer drugs 4-methyl-2,5-dimethoxy-amphetamine (DOM), 4-iodo-2,5-dimethoxy-amphetamine (DOI), 4-chloro-2,5-dimethoxy-amphetamine (DOC), 4-bromo-2,5-dimethoxy-amphetamine (DOB), 4-bromo-2,5-dimethoxy-methamphetamine (MDOB), and 2,4,5-trimethoxy-amphetamine (TMA-2) are potent serotonin 5HT 2 receptor agonists and have appeared on the illicit drug market. These drugs are mainly metabolized by O-demethylation or in case of DOM by hydroxylation of the methyl moiety. In an initial activity screening using microsomes of insect cells heterologously expressing human CYPs, CYP2D6 was found to be the only CYP isoenzyme involved in the above-mentioned main metabolic steps whereas the amounts of metabolites formed were very small. As inhibition of CYP2D6 by other amphetamines had been described, the inhibitory effects of the 2,5-dimethoxyamphetamine derivatives were studied using insect cell microsomes with heterologously expressed human CYP2D6 and pooled human liver microsomes (HLM) as enzyme sources and dextromethorphan O-demethylation as probe reaction. All studied drugs were observed to be non-mechanism-based competitive inhibitors of CYP2D6 with inhibition constants ( K i) from 7.1 to 296 μM using recombinant CYP2D6 and 2.7–19.9 μM using HLM. For comparison, the K i values for quinidine and fluoxetine were 0.0092 and 8.2 μM using recombinant CYP2D6 and 0.019 and 0.93 μM using HLM. As the K i values of the drugs were much higher than that of quinidine and, with the exception of DOI, higher than that of fluoxetine, interactions with other CYP2D6 substrates are possible but rather unlikely.