Naslov
Evaluation of toxic profile of phenylethylamine entactogens by predicting on- and off-targets and by ADMET and QSAR studies

Autori
Jadrijević-Mladar Takač, Milena ; Takač, Tin

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Book of Abstracts, 7th BBBB International Conference on Pharmaceutical Sciences, Acta Pharmaceutica Hungarica, 3-4 2017, APHGAO 87, (043)85-244. (2017) / Noszal, Bela ; Zelko, Romana - Budimpešta : Hungarian Society for Pharmaceutical Sciences, 2017, 159-160

Skup
7th 7th BBBB International Conference on Pharmaceutical Sciences, New Trends in Pharmaceutical Sciences and Pharmacy Practice

Mjesto i datum
Budimpešta, Mađarska, 05.10.2017. - 07.10.2017

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Entactogens ; Phenylethylamine derivatives ; Predicting on- and off-targets ; ADMET ; QSAR
(entactogens ; phenylethylamine derivatives ; predicting on- and off-targets ; ADMET ; QSAR)

Sažetak
BACKGROUND: A considerable research demonstrates that entactogens have serious toxic effects, both acute and chronic, that resemble those previously seen with other amphetamines. Among many others the four principal types of such serious toxicity are hepatic, cardiovascular, cerebral and hyperpyrexic. AIMS: The aim of this study was to predict on- and off-targets as well as ADMET properties of selected phenylethylamine entactogens (n = 25) in order to get more insights in their toxic profile. RESULT: The sodium dependent serotonin or dopamine transporters and trace amine-associated receptors were revealed by Swiss Target Prediction software as biological targets with the highest probability. Both, CYP inhibitor (1A2, 2D6) and CYP substrate properties (1A2, 2B6, 2C9, 2C19, and 2D6 and 2E1) have been predicted for majority of entactogens. QSAR studies, using computed molecular descriptors (LogP, Mr, TPSA, V) and topological indices (F, X, J, H, WW, W, Wp and Sz) with predicted ADMET properties computed by ADMET PredictorTM 8.1 (Simulations Plus, USA) revealed the most significant correlations between ADMET Risk vs. CYP Risk (R = 0.99), MLogP vs. TOX hERG (cardiotoxicity) and human plasma protein binding (R = 0.75 and R = 0.92, respectively). Predicted ADMET risk were between 1 and 4 (codes 1A, 2C19, 2D6, Mu or Hp), CYP risk between 1 and 2.72 (codes 1A2, 2D6 and 2C19) and TOX risk between 0 and 3.45 with codes of mutagenicity (Mu) and hepatotoxicity (Hp). Mu was predicted for MDMEO or 1-(1, 3-benzodioxol-5-yl)-N-methoxypropan-2-amine (14) and MDOH or 3, 4-methylenedioxy-N-hydroxyamphetamine (15) while both Hp and Mu were predicted for MDCPM or 3, 4-methylenedioxy-N-cyclopropylmethylamphetamine (18). CONCLUSIONS: The results of this study revealed many unfavourable properties of evaluated molecules and MDCPM (18) as entactogen with the worst toxic profile. REFERENCES: 1. Aouidate A. et al., J Taibah Univ Sci 10, 787-96 (2016) 2. LeDonne Jr N et al., J Cheminf 3, 7 (2011)

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Farmacija

POVEZANOST RADA