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Abstract(s)
Na última década, verificou-se globalmente um aumento do consumo de novas substâncias psicoativas (NSP) como drogas de abuso. A 2ª classe mais abundante entre as NSP relatadas ao EMCDDA (European Monitoring Centre for Drugs and Drug Addiction) são as catinonas sintéticas. Estas NSP representam uma ameaça à saúde pública pois pretendem mimetizar o efeito de drogas ilícitas, no entanto, as consequências associadas ao seu consumo são ainda pouco conhecidas e, tendo ocorrido várias fatalidades relacionadas à sua utilização.
De modo a aumentar o conhecimento sobre as catinonas sintéticas foi avaliado o potencial efeito citotóxico in vitro, usando a linha celular de hepatocarcinoma humano (HepG2) e a linha celular diferenciada de neuroblastoma humano (SH-SY5Y), e ainda o efeito sobre a atividade da enzima acetilcolinesterase (AChE), de 21 catinonas: 2’-CMC, 3’-CMC, 4’-CMC, 2’-CEC, 3’-CEC, 4’-CEC, 3’-CBC, 4’-CBC, 2’-Cl-PPP, 3’-Cl-PPP, 4’-Cl-PPP, 2’-CDC, 3’-CDC, 4’-CDC, 3’-Cl-DEC, 4’-Cl-DEC, 3’-CIC, 4’-CIC, 3’-Cl-TBC, 4’-Cl-TBC e a mefedrona. Destas, foram sintetizadas e caracterizadas por RMN as cloro-N-butilcatinonas (CBC).
Foi possível comprovar uma relação entre as atividades obtidas e a estrutura das catinonas testadas, tendo-se demonstrado pela primeira vez, que as catinonas inibem a atividade da AChE. Verificou-se que as catinonas que apresentaram melhor capacidade inibitória têm uma cadeia
N, N-dialquílica com quatro átomos de carbono (3’-Cl-DEC, 4’-Cl-DEC) ou uma cadeia N-isopropílica (3’-CIC).
Verificou-se, de um modo geral, um aumento da citotoxicidade em ambas as linhas celulares, com o aumento da cadeia N-alquílica do grupo amino, sendo as catinonas sintetizadas, 3’-CBC e 4’-CBC, as mais ativas. A comparação dos valores do LC50 da mefedrona e da 4’-CMC sugere
que a substituição de um grupo metilo por um átomo de cloro no anel aromático aumenta a citotoxicidade.
Apesar de existirem diferenças significativas nas atividades obtidas entre a maioria dos regioisómeros, que diferem na posição do átomo do cloro no anel aromático (orto, meta e para), não se verificou uma tendência regular no efeito desta posição sobre a atividade.
Foi ainda realizada uma previsão in silico das propriedades farmacocinéticas ADME (absorção, distribuição, metabolismo e excreção) das catinonas usadas neste trabalho, nomeadamente as suas
propriedades físico-químicas e o seu potencial de bioatividade. Os dados obtidos no geral indicam que todas as catinonas poderão exibir uma boa disponibilidade oral, evidenciando que o seu consumo, para além dos efeitos experimentalmente determinados neste trabalho, constituem um
risco para saúde dos consumidores. É de ressalvar ainda a necessidade de continuar a investigar outros efeitos biológicos potencialmente associados ao consumo destas substâncias.
Over the past decade, there has been a global increase in the consumption of new psychoactive substances (NPS) as drugs of abuse. Synthetic cathinones are the second most prevalent class of NPS reported to the European Monitoring Center for Drugs and Drug Addiction (EMCDDA). These NPS represent a threat to public health as they aim to mimic the effect of illicit drugs where the consequences associated with their consumption are still poorly understood, and several fatalities have already been related to their use. In order to increase knowledge about synthetic cathinones, the potential cytotoxic effect was evaluated in vitro using the human hepatocarcinoma cell line (HepG2) and the differentiated human neuroblastoma cell line (SH-SY5Y), as well as the effect on the enzyme activity acetylcholinesterase (AChE), of 21 cathinones: 2'-CMC, 3'-CMC, 4'-CMC, 2'-CEC, 3'-CEC, 4'-CEC, 3'-CBC, 4'-CBC, 2'-Cl-PPP, 3'-Cl-PPP, 4'-Cl-PPP, 2'-CDC, 3'-CDC, 4'-CDC, 3'-Cl-DEC, 4'-Cl-DEC, 3'-CIC, 4'-CIC, 3'-Cl-TBC, 4'-Cl-TBC and mephedrone. Of these, chloro-N-butylcathinones (CBC) were synthesized and characterized by NMR. A relationship between the activities obtained and the structure of the cathinones assessed was proven, demonstrating for the first time that cathinones inhibit AChE activity. It was found that cathinones with the best inhibitory capacity have an N,N-dialkyl chain with four carbon atoms (3'-Cl-DEC, 4'-Cl-DEC) or an N-isopropyl chain (3'-CIC). In general, there was an increase in cytotoxicity in both cell lines, with an increase in the N-alkyl chain of the amino group, with the synthesized cathinones 3'-CBC and 4'-CBC being the most active. Additionally, a comparison of the LC50 values of mephedrone and 4'-CMC seems to indicate that the replacement of a methyl group by a chlorine atom in the aromatic ring increases cytotoxicity. Although there are significant differences in the activities obtained between the majority of regioisomers that differ in the position of the chlorine atom in the aromatic ring (ortho, meta and para), there was no regular trend in the effect of this position on the activity. An in silico prediction of the ADME pharmacokinetic properties (absorption, distribution, metabolism and excretion) of the cathinones used in this work was also analysed, namely their physicochemical properties and their potential for bioactivity. The data obtained in general indicate that all cathinones may exhibit good oral availability, revealing that their consumption, in addition to the experimentally determined effects in this work, constitutes a risk to the health of consumers. It is also noteworthy the need to continue investigating other potentially associated biological effects of the consumption of these substances.
Over the past decade, there has been a global increase in the consumption of new psychoactive substances (NPS) as drugs of abuse. Synthetic cathinones are the second most prevalent class of NPS reported to the European Monitoring Center for Drugs and Drug Addiction (EMCDDA). These NPS represent a threat to public health as they aim to mimic the effect of illicit drugs where the consequences associated with their consumption are still poorly understood, and several fatalities have already been related to their use. In order to increase knowledge about synthetic cathinones, the potential cytotoxic effect was evaluated in vitro using the human hepatocarcinoma cell line (HepG2) and the differentiated human neuroblastoma cell line (SH-SY5Y), as well as the effect on the enzyme activity acetylcholinesterase (AChE), of 21 cathinones: 2'-CMC, 3'-CMC, 4'-CMC, 2'-CEC, 3'-CEC, 4'-CEC, 3'-CBC, 4'-CBC, 2'-Cl-PPP, 3'-Cl-PPP, 4'-Cl-PPP, 2'-CDC, 3'-CDC, 4'-CDC, 3'-Cl-DEC, 4'-Cl-DEC, 3'-CIC, 4'-CIC, 3'-Cl-TBC, 4'-Cl-TBC and mephedrone. Of these, chloro-N-butylcathinones (CBC) were synthesized and characterized by NMR. A relationship between the activities obtained and the structure of the cathinones assessed was proven, demonstrating for the first time that cathinones inhibit AChE activity. It was found that cathinones with the best inhibitory capacity have an N,N-dialkyl chain with four carbon atoms (3'-Cl-DEC, 4'-Cl-DEC) or an N-isopropyl chain (3'-CIC). In general, there was an increase in cytotoxicity in both cell lines, with an increase in the N-alkyl chain of the amino group, with the synthesized cathinones 3'-CBC and 4'-CBC being the most active. Additionally, a comparison of the LC50 values of mephedrone and 4'-CMC seems to indicate that the replacement of a methyl group by a chlorine atom in the aromatic ring increases cytotoxicity. Although there are significant differences in the activities obtained between the majority of regioisomers that differ in the position of the chlorine atom in the aromatic ring (ortho, meta and para), there was no regular trend in the effect of this position on the activity. An in silico prediction of the ADME pharmacokinetic properties (absorption, distribution, metabolism and excretion) of the cathinones used in this work was also analysed, namely their physicochemical properties and their potential for bioactivity. The data obtained in general indicate that all cathinones may exhibit good oral availability, revealing that their consumption, in addition to the experimentally determined effects in this work, constitutes a risk to the health of consumers. It is also noteworthy the need to continue investigating other potentially associated biological effects of the consumption of these substances.
Description
Trabalho Final de Mestrado para obtenção do grau de Mestre em Engenharia Química e Biológica – Perfil Bioprocessos
Keywords
NSP Catinonas Sintéticas AChE HepG2 SH-SY5Y ADME in silico Synthetic Cathinones
Citation
GOMES, Ana Patrícia Soares Tauleigne –Avaliação da toxicidade de catinonas sintéticas usadas como drogas de abuso. Lisboa: Instituto Superior de Engenharia de Lisboa. 2023. Dissertação de Mestrado.
Publisher
Instituto Superior de Engenharia de Lisboa