Publicação
Síntese e Caracterização de Catinonas e Metabolitos
| Resumo: | Synthetic cathinones constitute a relevant class of New Psychoactive Substances, often associated with poorly understood toxicological risks. These compounds are typically consumed in their racemic form. Since stereochemistry plays a crucial role in metabolism and toxicity, it is essential to deepen the study of their biotransformation pathways and the potential formation of metabolites more toxic than the parent cathinones. In this context, three cathinones were investigated with the following objectives: (i) to study the stereoselective synthesis and HPLC-DAD separation of the reduced metabolites of mephedrone in order to obtain enantiomerically pure standards; (ii) to evaluate the role of the catechol metabolite in the biotransformation and toxicity of methylone; and (iii) to determine the metabolic profile of 4-PH-PVP, a cathinone recently identified in Portugal. In the mephedrone studies, reduction of the carbonyl group with different reducing agents consistently produced the same pair of stereoisomers. Although several chromatographic conditions were tested using a chiral column, an efficient separation of the mephedrone enantiomers or their reduced metabolites could not be achieved. However, upon testing twelve other cathinones and some of their metabolites, conditions were optimized that enabled the isolation of 4-CIC and its corresponding reduced metabolites. Reanalysis of the isolated products by HPLC-DAD revealed possible racemization, which may explain the inefficiency of the isolation process. The metabolism study of methylone and its catechol metabolite by LC-HRMS/MS revealed half-lives of 66.0 min and 71.5 min, respectively, with only the monohydroxylated metabolite of methylone being identified. No potentially toxic compounds derived from the catechol quinone, nor adducts with N-acetylcysteine, were detected. For 4-PH-PVP, in vitro incubations allowed the determination of a half-life of 24.1 min and the identification of nine Phase I and three Phase II metabolites through LC-HRMS/MS analysis. |
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| Autores principais: | Ferreira,Carlota Pinto da Cruz Portugal |
| Assunto: | Metabolism Stereoselectivity Mephedrone Methylone 4-PH-PVP |
| Ano: | 2025 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso embargado |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | português |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Synthetic cathinones constitute a relevant class of New Psychoactive Substances, often associated with poorly understood toxicological risks. These compounds are typically consumed in their racemic form. Since stereochemistry plays a crucial role in metabolism and toxicity, it is essential to deepen the study of their biotransformation pathways and the potential formation of metabolites more toxic than the parent cathinones. In this context, three cathinones were investigated with the following objectives: (i) to study the stereoselective synthesis and HPLC-DAD separation of the reduced metabolites of mephedrone in order to obtain enantiomerically pure standards; (ii) to evaluate the role of the catechol metabolite in the biotransformation and toxicity of methylone; and (iii) to determine the metabolic profile of 4-PH-PVP, a cathinone recently identified in Portugal. In the mephedrone studies, reduction of the carbonyl group with different reducing agents consistently produced the same pair of stereoisomers. Although several chromatographic conditions were tested using a chiral column, an efficient separation of the mephedrone enantiomers or their reduced metabolites could not be achieved. However, upon testing twelve other cathinones and some of their metabolites, conditions were optimized that enabled the isolation of 4-CIC and its corresponding reduced metabolites. Reanalysis of the isolated products by HPLC-DAD revealed possible racemization, which may explain the inefficiency of the isolation process. The metabolism study of methylone and its catechol metabolite by LC-HRMS/MS revealed half-lives of 66.0 min and 71.5 min, respectively, with only the monohydroxylated metabolite of methylone being identified. No potentially toxic compounds derived from the catechol quinone, nor adducts with N-acetylcysteine, were detected. For 4-PH-PVP, in vitro incubations allowed the determination of a half-life of 24.1 min and the identification of nine Phase I and three Phase II metabolites through LC-HRMS/MS analysis. |
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