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

Empathogens or entactogens are class of psychoactive drugs that produce experiences of emotional communion, relatedness, emotional openness, empathy or sympathy, as reported for experiences with 3, 4- methylenedioxymethamphetamine (MDMA, Ecstasy) [1, 2]. Most clinical MDMA research in patients to date has focused on MDMA-assisted psychotherapy to treat posttraumatic stress disorder (PTSD) and it is now entering the final Phase 3 stage of drug development for marketing approval by the FDA and EMA in 2021 [3]. Research data demonstrates that entactogens have serious toxic effects on humans, both acute and chronic, that resemble to those seen with other amphetamines. However, many of new entactogens, derivatives of MDMA, appeared on the illicit drug market rapidly with largely unknown properties. 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, USA) was used for prediction of molecular descriptors and toxicological parameters used in QSAR studies. The results of this study revealed that these molecules are both CYP inhibitors (1A2, 2D6) and CYP substrates (CYP1A2, 2B6, 2C9, 2C19, 2D6 and 2E1). The following risk scores were predicted: ADMET risk (1 – 4 ; 1A, 19, D6, Mu, Hp and Vd) ; CYP risk (1 – 2.72 ; 1A2, 19 and D6), TOX MUT Risk (0.0 – 4.0 ; m1, S2, S3 and S4) and TOX risk (0.0 – 2.0 ; Mu and Hp). Mu has been predicted for 3, 4-methylenedioxy-N-methoxyamphetamine (MDMEO) and 3, 4-methylenedioxy-Nhydroxyamphetamine (MDOH) while Hp and Mu were predicted for 3, 4-methylenedioxy-Ncyclopropylmethylamphetamine (MDCPM). In this in silico study investigated entactogens were revealed as non-biodegradable molecules. The best correlations were obtained with MlogP which was computed in the range between 0.839 and 2.997. Except for MDMEO, MDOH and MDCPM, safety profles of other investigated entactogens were similar to MDMA. F. X. Vollenweider, Brain mechanisms of hallucinogens and entactogens. Dialogues Clin Neurosci 3 (2001) 265-279. A. Aouidate, A. Ghaleb, M. Ghamali, S. Chtita, M. Choukrad, A. Sbai, M. Bouachrine, T. Lakhlifi. Combining DFT and QSAR studies for predicting psychotomimetic activity of substituted phenethylamines using statistical methods, J Taibah Univ Sci 10 (2016) 787-796. A Phase 3 Program of MDMA-Assisted Psychotherapy for the Treatment of Severe Posttraumatic Stress Disorder (PTSD), https://maps.org/research/mdma/ptsd/phase3

entactogens, empathogens, ADMET, toxicity, QSAR

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