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Síntese e atividade neurotóxica de metabolitos de catinonas sintéticas
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As Novas Substâncias Psicoativas (NSP), são substâncias que não são controladas pelas
Convenções sobre drogas das Nações Unidas, no entanto, representam um potencial risco para
a saúde pública semelhante às presentes nestas convenções. As catinonas sintéticas, são o
segundo maior grupo de NSP controladas pelo Observatório Europeu da Droga e da
Toxicodependência (EMCDDA). A facilidade com que é possível introduzir pequenas alterações
na estrutura química destes compostos, explica o número crescente de catinonas já reportadas.
Embora existam estudos na literatura a reportar o perfil neurotóxico de catinonas, a informação
sobre o efeito dos seus metabolitos é escassa. Algumas catinonas são extensivamente
metabolizadas no nosso organismo, pelo que os seus efeitos tóxicos se podem dever à ação dos
seus metabolitos. Assim, para o desenvolvimento de opções terapêuticas em casos de
intoxicação, é necessário esclarecer o papel toxicológico dos metabolitos. Decidiu-se, por isso,
sintetizar as catinonas 4’-metilmetcatinona (mefedrona), 4’-cloro-metilcatinona (4’-CMC) e α-
pirrolidonopentiofenona (α-PVP), por já serem consideradas drogas, bem como os seus
metabolitos maioritários para se proceder a uma avaliação da sua toxicidade.
Todos os compostos sintetizados foram caracterizados por espetroscopia de ressonância
magnética nuclear (RMN) e por espetrometria de massa de alta resolução (ESI-HRMS).
Nomeadamente, as catinonas (mefedrona, 4’-CMC e α-PVP), os metabolitos resultantes da
redução do grupo carbonilo (di-hidro-mefedrona, di-hidro-4’-cloro-metilcatinona, di-hidro-α-
pirrolidonopentiofenona), os resultantes da N-desmetilação (nor-mefedrona, nor-4’-cloro-
metilcatinon) e ainda os que sofreram redução e N-desmetilação (di-hidro-nor-mefedrona e di-
hidro-nor-4’-cloro-metilcatinona).
A atividade citotóxica, das catinonas, bem como dos respetivos metabolitos reduzidos e N-
desmetilados, foi avaliada em linhas celulares SH-SY5Y. É importante salientar que foi a primeira
vez que se avaliou a toxicidade destes metabolitos em linhas celulares cerebrais. Os resultados
obtidos revelaram que todos os metabolitos reduzidos são mais tóxicos (LD50 0,60-2,42 mM)
que as drogas que lhes dão origem (LD50 2,87-4,52 mM), sugerindo assim que a redução do
grupo cetónico tem um papel crucial na citotoxicidade associada com o consumo das catinonas
estudadas.
New Psychoactive Substances are substances that are not controlled by the United Nations Drug Conventions, however, they pose a potential risk to public health similar to those present in these conventions. Synthetic cathinones are the second largest group of NPS controlled by the European Observatory on Drugs and Drug Addiction (EMCDDA). The ease with which it is possible to introduce small changes in the chemical structure of these compounds, explains the increasing number of cathinones that have already been reported. Although there are studies in the literature reporting the neurotoxic profile of cathinones, information on the effect of their metabolites is scarce. Some cathinones are extensively metabolized in our body, so their toxic effects may be due to the action of their metabolites. Thus, for the development of therapeutic options for cases of intoxication, it is necessary to clarify the toxicological role of metabolites. It was therefore decided to synthesize the cathinones 4’-methylmethcathinone (mefedrona), 4’- chloro-methylcathinone (4’-CMC) and α-pyrrolinopentiophenone (α-PVP), as they are already considered drugs, as well as their major metabolites for an assessment of their toxicity. All synthesized compounds were characterized by nuclear magnetic resonance spectroscopy (NMR) and high resolution mass spectrometry (ESI-HRMS).Namely, the metabolites resulting from the reduction of the carbonyl group (dihydro-mephedrone, dihydro-4’-chloro- methylcathinone, dihydro-α-PVP), those resulting from N-demethylation (nor-mephedrone, nor- 4’-cloromethylcathinone) and also those that underwent reduction and N-demethylation (dihydro- nor-mephedrone and dihydro-nor-4’-chloromethylcathinone). The cytotoxic activity of the cathinones, as well as their reduced and N-demethylated metabolites, was evaluated on cell lines SH-SY5Y. It is important to note that this was the first time that the cytotoxicity of these metabolites was evaluated in brain cell lines. The results obtained revealed that all reduced metabolites are more toxic (LD50 0.60-2,42 mM) than their respective parent drugs (LD50 2,87-4,52 mM), suggesting that the reduction of the ketone group plays a crucial role in the toxicity associated with the consumption of the cathinones studied.
New Psychoactive Substances are substances that are not controlled by the United Nations Drug Conventions, however, they pose a potential risk to public health similar to those present in these conventions. Synthetic cathinones are the second largest group of NPS controlled by the European Observatory on Drugs and Drug Addiction (EMCDDA). The ease with which it is possible to introduce small changes in the chemical structure of these compounds, explains the increasing number of cathinones that have already been reported. Although there are studies in the literature reporting the neurotoxic profile of cathinones, information on the effect of their metabolites is scarce. Some cathinones are extensively metabolized in our body, so their toxic effects may be due to the action of their metabolites. Thus, for the development of therapeutic options for cases of intoxication, it is necessary to clarify the toxicological role of metabolites. It was therefore decided to synthesize the cathinones 4’-methylmethcathinone (mefedrona), 4’- chloro-methylcathinone (4’-CMC) and α-pyrrolinopentiophenone (α-PVP), as they are already considered drugs, as well as their major metabolites for an assessment of their toxicity. All synthesized compounds were characterized by nuclear magnetic resonance spectroscopy (NMR) and high resolution mass spectrometry (ESI-HRMS).Namely, the metabolites resulting from the reduction of the carbonyl group (dihydro-mephedrone, dihydro-4’-chloro- methylcathinone, dihydro-α-PVP), those resulting from N-demethylation (nor-mephedrone, nor- 4’-cloromethylcathinone) and also those that underwent reduction and N-demethylation (dihydro- nor-mephedrone and dihydro-nor-4’-chloromethylcathinone). The cytotoxic activity of the cathinones, as well as their reduced and N-demethylated metabolites, was evaluated on cell lines SH-SY5Y. It is important to note that this was the first time that the cytotoxicity of these metabolites was evaluated in brain cell lines. The results obtained revealed that all reduced metabolites are more toxic (LD50 0.60-2,42 mM) than their respective parent drugs (LD50 2,87-4,52 mM), suggesting that the reduction of the ketone group plays a crucial role in the toxicity associated with the consumption of the cathinones studied.
Descrição
Palavras-chave
Catinonas Metabolitos RMN Síntese SH-SY5Y Citotoxicidade