Acta Pharm. 69 (2019) 563-584
Original research paper
Evaluation of phenylethylamine type entactogens and their metabolites relevant to ecotoxicity – a QSAR study
MILENA JADRIJEVIĆ-MLADAR TAKAČ, JOAO DANIEL CASIMIRO MAGINA and TIN TAKAČ
1 University of Zagreb Faculty of Pharmacy, Department of Medicinal Chemistry, 10 000 Zagreb, Croatia
2 Universidade de Lisboa, Faculdade de Farmacia, 1649-004 Lisboa, Portugal
3 University of Zagreb Faculty of Chemical Engineering and Technology, 10 000 Zagreb, Croatia
Accepted July 20, 2019
Published online September 5, 2019
The impact of the selected entactogens and their o-quinone metabolites on the environment was explored in QSAR studies by the use of predicted molecular descriptors, ADMET properties and environmental toxicity parameters, i.e., acute toxicity in Tetrahymena pyriformis (TOX_ATTP) expressed as Th_pyr_pIGC50/mmol L–1, acute toxicity in Pimephales promelas, the fathead minnow (TOX_FHM) expressed as Minnow LC50/mg L–1, the acute toxicity in Daphnia magna (TOX_DM) expressed as Daphnia LC50/mg L–1 and bioconcentration factor (BCF).
The formation of corresponding o-quinones via benzo-dioxolone ring, O-demetylenation was predicted as the main metabolic pathway for all entactogens except for 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propan-2-amine (DiFMDA). The least favourable ADMET profile was revealed for N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-O-methylhydroxyl-amine (MDMEO).
QSAR studies revealed significant linear correlations between MlogP of entactogens and MlogP of o-quinone metabolites (R = 0.99), and Th_pyr_pIGC50/mmol L–1 (R = 0.94), also their MlogPs with Minnow_LC50/mg L–1 (R = 0.80 and R = 0.78), BCF (R = 0.86 and R = 0.82) and percentage of o-quinones' yields (R = 0.73 and R = 0.80). Entactogens were predicted as non-biodegradable molecules, whereas the majority of their o-quinones were biodegradable.
Keywords: entactogens, ecstasy, ADMET, CYP metabolism, ecotoxicity, QSAR