Estudos computacionais e síntese de potenciais agonistas de receptores nicotínicos de acetilcolina (subtipo α7) visando o tratamento da doença de Alzheimer
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Data
2021-11-25
Autores
Vellosa, Ana Beatriz Silva
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Universidade Estadual Paulista (Unesp)
Resumo
Os receptores nicotínicos de acetilcolina estão relacionados a doenças como esquizofrenia, dependência química (álcool e tabaco), epilepsia, doença de Alzheirmer, ansiedade e doença de Parkinson. Dentre os receptores nicotínicos de acetilcolina presentes no sistema nervoso central, o subtipo α7 é um dos mais abundantes. Como exemplo relevante das doenças supracitadas, a DA tem cerca de um novo caso a cada três segundos no mundo, de acordo com dados da Alzheimer’s Disease International. Os receptores nicotínicos de acetilcolina do subtipo α7 apresentam efeitos neuroprotetores, o que ameniza a neurotoxicidade induzida pela proteína β-amiloide, dessa forma, a modulação por agonistas desse receptor é considerada uma abordagem promissora para o tratamento da doença de Alzheimer. Nesse contexto, visando a obtenção de compostos inéditos com atividade agonista em receptores nicotínicos de acetilcolina do subtipo α7 para o tratamento da doença de Alzheimer, este trabalho foi iniciado com a tentativa de síntese de 8 fragmentos, de padrão estrutural pirrolidínico, selecionadas após estudos detalhados de ancoragem molecular, descritos em trabalho prévio do grupo de pesquisa (LaQMedSOMM). A etapa seguinte consistiu na ancoragem molecular de fragmentos intermediários das reações citadas acima e análise das interações resultantes. Os resultados obtidos da etapa computacional mostram que a subunidade do grupo protetor t-butiloxicarbonil realiza interações importantes com resíduos chaves de aminoácidos e que moléculas com substituintes fluorados ocuparam melhores colocações na classificação em ordem crescente de número de interações. Já as substâncias com substituinte nitro na posição orto foram às únicas que apresentaram interações não favoráveis, ocupando as últimas posições na classificação. Quatro fragmentos foram sintetizados, isolados e caracterizados por RMN 1H. As tentativas de redução do grupo carbonila das amidas não lograram êxito, gerando sempre mistura de muitos subprodutos.
Nicotinic acetylcholine receptors are related to diseases such as schizophrenia, chemical dependency (alcohol and tobacco), epilepsy, Alzheimer's disease, anxiety and Parkinson's disease. Among the nicotinic acetylcholine receptors present in the Central Nervous System, the α7 subtype is one of the most abundant. As a relevant example of the aforementioned diseases, Alzheimer's disease has about one new case every three seconds in the world, according to data from Alzheimer's Disease International. Subtype α7 nicotinic acetylcholine receptors have neuroprotective effects, mitigating the neurotoxicity induced by the β-amyloid protein, thus modulation by agonists of this receptor is considered a promising approach for the treatment of Alzheimer's disease. In this context, aiming to obtain novel compounds with agonist activity at α7 subtype nicotinic acetylcholine receptors for the treatment of Alzheimer's disease, this work began with an attempt to synthesize 8 fragments, with a pyrrolidine structural pattern, selected after detailed studies of molecular modeling, described in a previous work by the research group (LaQMedSOMM). The next step consisted of molecular anchoring of intermediate fragments of the reactions mentioned above and analysis of the resulting interactions. The results obtained from the computational step show that the t-butyloxycarbonyl protecting group subunit performs important interactions with key amino acid residues and that molecules with fluorinated substituents occupied better placements in the classification in ascending order of number of interactions. Substances with a nitro substituent in the ortho position were the only ones that presented non favorable interactions, occupying the last positions in the classification. Four fragments were synthesized, isolated and characterized by 1H NMR. Attempts to reduce the carbonyl group of amides were unsuccessful, always generating a mixture of many by-products.
Nicotinic acetylcholine receptors are related to diseases such as schizophrenia, chemical dependency (alcohol and tobacco), epilepsy, Alzheimer's disease, anxiety and Parkinson's disease. Among the nicotinic acetylcholine receptors present in the Central Nervous System, the α7 subtype is one of the most abundant. As a relevant example of the aforementioned diseases, Alzheimer's disease has about one new case every three seconds in the world, according to data from Alzheimer's Disease International. Subtype α7 nicotinic acetylcholine receptors have neuroprotective effects, mitigating the neurotoxicity induced by the β-amyloid protein, thus modulation by agonists of this receptor is considered a promising approach for the treatment of Alzheimer's disease. In this context, aiming to obtain novel compounds with agonist activity at α7 subtype nicotinic acetylcholine receptors for the treatment of Alzheimer's disease, this work began with an attempt to synthesize 8 fragments, with a pyrrolidine structural pattern, selected after detailed studies of molecular modeling, described in a previous work by the research group (LaQMedSOMM). The next step consisted of molecular anchoring of intermediate fragments of the reactions mentioned above and analysis of the resulting interactions. The results obtained from the computational step show that the t-butyloxycarbonyl protecting group subunit performs important interactions with key amino acid residues and that molecules with fluorinated substituents occupied better placements in the classification in ascending order of number of interactions. Substances with a nitro substituent in the ortho position were the only ones that presented non favorable interactions, occupying the last positions in the classification. Four fragments were synthesized, isolated and characterized by 1H NMR. Attempts to reduce the carbonyl group of amides were unsuccessful, always generating a mixture of many by-products.
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Palavras-chave
Doença de Alzheimer, Receptores nicotínicos, Síntese orgânica, Demência, Química medicinal