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Evaluation of Entactogens of Phenylethylamine Type and their Metabolites Relevant to Ecotoxicity – QSAR Study

Newer serotonergic club drugs (entactogens) facilitate feelings of empathy and ‘touching the inner self’. They belong to distinct psychoactive substance class that evoke mainly pleasant emotional effects of relaxation, feelings of happiness, closeness to others and increased emotional openness (empathy or sympathy). Many of new entactogens are derivatives of (±) 3, 4-methylenedioxymeth-amphetamine (MDMA, Ecstasy) that appeared on the illicit drug market rapidly with largely unknown propeties. A considerable research data demonstrate that entactogens have serious toxic effects on humans, both acute and chronic, that resemble to those seen with other amphetamines. So far there is not to much information about ecotoxic profile of entactogens. The aim of this study was to predict ADMET properties of selected entactogens (n = 25) and their major metabolites in humans in order to evaluate their impact on environment and health. The ADMET PredictorTM, SimulationsPlus Inc., USA was used for prediction of molecular descriptors and toxicological parameters used in QSAR studies. ADMET-related descriptors relevant to environmental toxicity were computed using four models: the fathead minnow acute toxicity model based on lethal effects on Pimephales promelas (Minnow LC50, TOX_FHM), the concentration needed to inhibit 50% growth in the protozoa species Tetrahymena pyriformis (Th_pyr_pIGC50), the lethal concentration that results in the death of 50% of Daphnia magna (Daphnia LC50, TOX_DM) and bioconcentration factor (BCF). In this in silico study investigated entactogens were revealed as non-biodegradable molecules (TOX_Biodeg – No 96%) and predicted scores for bioconcentration factor (BCF) were computed in the range from 4.644 to 68.655. The best correlations were obtained with MlogP which was computed in the range between 0.839 and 2.997. The CYP metabolism involved all CYP-metatabolizing enzymes relevant to drug metabolism in humans and the opening of the benzo-dioxolone ring which was predicted as one of the main metabolic pathway of entactogens that can lead to the catechole moiety formation and in further oxydation to toxic electrophile quinones. Environmetal toxicity parameters: TOX FHM expressed as Minnow LC50 was computed from 2.654 to 172, 266 mg/L, TOX_ATPP expressed as pIGC50 from -0.104 to 1.173 mmol/L and TOX_DM expressed as Daphnia LC50 from 2.253 to 29.105 mg/L. References: 1. Aouidate A, Ghaleb A, Ghamali M, Chtita S, Choukrad M, Sbai A, Bouachrine M, Lakhlifi T. Combining DFT and QSAR studies for predicting psychotomimetic activity of substituted phenethylamines using statistical methods, J Taibah Univ Sci 2016 ; 10:787-796. 2. LeDonne Jr NC, Rissolo K., Bulgarelli J, Tini L. Use of structure-activity landscape index curves and curve integrals to evaluate the performance of multiple machine learning prediction models. J Cheminf 2011 ; 3:7.

Entactogens ; Phenylethylamines ; Ecotoxicity ; ADMET ; Metabolism ; CYP450 ; QSAR

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