Benzofuran analogues of amphetamine and methamphetamine: studies on the metabolism and toxicological analysis of 5-APB and 5-MAPB in urine and plasma using GC-MS and LC-(HR)-MSn techniques

Abstract

5-APB (5-(2-aminopropyl)benzofuran) and its N-methyl derivative 5-MAPB (N-methyl-5-(2-aminopropyl)benzofuran) are analogues of amphetamine and methamphetamine, respectively, and belong to the so-called novel psychoactive substances (NPS). They were consumed as stimulants or entactogens with euphoric and empathogenic effects. Being controlled in some countries, both compounds should be covered by drug testing in clinical and forensic toxicology. Therefore, metabolism studies have been performed by working up rat urine samples after a high single dose of the corresponding NPS with solid-phase extraction without and after enzymatic conjugates cleavage. The phase I metabolites were separated and identified after acetylation by GC-MS and/or LC-HR-MS(n) and the phase II metabolites by LC-HR-MS(n). The main metabolite of 5-APB was 3-carboxymethyl-4-hydroxy amphetamine and the main metabolites of 5-MAPB were 5-APB (N-demethyl metabolite) and 3-carboxymethyl-4-hydroxy methamphetamine. The cytochrome P450 (CYP) isoenzymes involved in the 5-MAPB N-demethylation were CYP1A2, CYP2B6, CYP2C19, and CYP2D6, and according to the kinetic parameters, CYP2B6 was responsible for the main part of the total CYP-dependent clearance. An intake of a common users' dose of 5-APB or 5-MAPB could be confirmed in rat urine using the authors' GC-MS and the LC-MS(n) standard urine screening approaches with the corresponding parent drugs as major target. In authentic human urine samples after ingestion of unknown doses of 5-MAPB, both metabolites could also be detected besides the parent drug. The plasma concentrations determined in six clinical cases ranged from 5 to 124 μg/L for 5-MAPB and from 1 to 38 μg/L for its N-demethyl metabolite 5-APB.

Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances – The case of the benzofuran 5-MAPB

“…For the present study, we have chosen 1-(1-benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB) which is a N-methylated version of 5-APB, structurally related to MDMA (Welter et al, 2015a(Welter et al, , 2015b. Online drug user fora suggest that 5-MAPB, despite its illegality, is still being used today.…”

Differentiation of 2- and 6-isomers of (2-dimethylaminopropyl)benzofuran by tandem mass spectrometry

“…1) два изомера, 5-(2-аминопропил)бен-зофуран (5-APB) и 6-(2-аминопро-пил)бензофуран (6-APB), а также их N-метильные производные (5-MAPB и 6-MAPB, соответственно). Соеди-нения 5-АРВ и 6-АРВ являются анта-гонистами серотониновых рецепто-ров и по своему фармакологическому действию подобны стимуляторам ам-фетаминового ряда [3,4]. На террито-рии России оборот 5-АРВ, 6-АРВ и их N-метильных производных контроли-руется законодательством.…”

“…The probable structure of the major fragment ions in the CID spectra of the compounds 2-MAPB and 6-MAPB значений параметров хроматографи-ческого удерживания этих соединений (рис. 2), а также их ацильных произ-водных [3,4]. Осенью 2015 года в нелегальном обороте нами впервые было обна-ружено еще одно соединение, изо-мерное 5-MAPB и 6-MAPB, а именно 2-(2-метиламинопропил)бензофуран (2-МAPB), структура которого была достоверно установлена с использо-ванием масс-спектрометрии высокого разрешения и двумерной ЯМР-спек-троскопии.…”

“…6-APB are serotonin receptor agonists and their pharmacological effects are similar to amphetamine-type stimulants [3,4]. In the territory of the Russia the circulation of 5-APB, 6-APB and these N-methyl derivatives is controlled by legislation.…”

“…When conducting analysis by gas chromatography-mass spectrometry using typical gas chromatography columns for drug identification with dimethylpolysiloxane nonpolar stationary phase (such as HP-5) the differentiation of compounds 5-APB and 6-APB or 5-MAPB and 6-MAPB is possible due to the differences in the values of parameters of the chromatographic retention of these compounds (Fig. 2) or their acyl derivatives [3,4].…”