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

Scientific paper - Original scientific paper

• Author: Milena Jadrijević-Mladar Takač
• Author: Joao Daniel Casimiro Magina
• Author: Tin Takač
• Author's institution: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry)
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract (english)

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 (english): entactogens; ecstasy; ADMET; CYP metabolism; ecotoxicity; QSAR
• Language: english
• Publication type: Scientific paper - Original scientific paper
• Publication status: Published
• Peer review: Peer review - international
• Publication version: Published version
• Journal title: Acta Pharmaceutica
• Numbering: vol. 69, no. 4, pp. 563-584
• p-ISSN: 1330-0075
• e-ISSN: 1846-9558
• DOI: https://doi.org/10.2478/acph-2019-0038
• URN:NBN: urn:nbn:hr:163:963230
• Publication: 2019
• Document URL: https://hrcak.srce.hr/225506
• Type of resource: Text
• Access conditions: Open access
• Created on: 2020-04-07 14:22:17