Evaluation of phenylethylamine type entactogens and their metabolites relevant to ecotoxicology – a QSAR study

Abstract

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-dioxo-lone ring, O-demethylenation 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-methylhydroxylamine (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.

Computational Approaches in Preclinical Studies on Drug Discovery and Development

“…(3) ADMET Predictor TM ( https://www.simulations-plus.com/software/admetpredictor/ ) is another tool utilizing QSAR to predict ADMET parameters of compounds. Takac et al ( 2019 ) used ADMET Predictor TM to investigate the potential impact and safety profile with respect to the environment and health for 25 selected entactogen molecules. The chemical structure (including 1D and 2D) information was used as the input for ADMET Predictor TM .…”