Novos ligantes de receptores de histamina: avaliação do papel do heterociclo e do grupo básico nas afinidades pelos receptores H3 e H4
Data
2021-06-30
Autores
Fernandes, Gustavo Ariel Borges 
Orientadores
Fernandes, João Paulo dos Santos
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A histamina é um mediador químico que exerce suas ações através da ativação de 4 diferentes receptores acoplados a proteína G (H1, H2, H3 e H4). O receptor H3 (H3R) é encontrado predominantemente no sistema nervoso central (SNC), podendo ter função como auto-receptor, modulando a liberação de histamina nos neurônios histaminérgicos e função como hetero-receptor, modulando a liberação de outros neurotransmissores. Atualmente, o único fármaco com atividade seletiva sobre H3R aprovado para uso terapêutico é o pitolisanto, e devido a sua ação antagonista sobre este receptor, é utilizado para o tratamento da narcolepsia. Entretanto, devido à sua função neurológica o H3R tem diversos potenciais como alvo terapêutico para o tratamento de diversas desordens do SNC, como as doenças de Alzheimer e de Parkinson, esquizofrenia e outras. O receptor H4 (H4R) é o mais recente a ser descoberto, e é encontrado principalmente em células do sistema imunológico, e assim fármacos com ação antagonista sobre este receptor podem ser potenciais tratamentos para doenças inflamatórias, como a asma, doença inflamatória intestinal e outras doenças inflamatórias crônicas. Diante dos potenciais terapêuticos do H3R e do H4R como alvos farmacológicos e do baixo número de fármacos com ação sobre estes receptores, fica evidente o interesse na busca por novos ligantes. Nosso grupo vem trabalhando no desenvolvimento de ligantes desses receptores, com resultados promissores com a série LINS01, com alguns compostos que tiveram afinidade em nanomolar e eficácia em modelos de memória e asma. O objetivo do presente trabalho foi avaliar a influência de modificações nas regiões aromática e básica desses compostos na afinidade pelo H3R e H4R. Assim, foram planejados compostos contendo os grupos 2,3-diidrobenzofurano, benzofurano, benzofuranil-amida, benziluréia e anilina na região aromática, e piperazinas, homopiperazinas e etilenodiaminas na região básica, considerando características farmacofóricas para a interação com os alvos. Os compostos foram obtidos utilizando metodologias clássicas, com rendimentos obtidos de 8-91%, e caracterizados utilizando técnicas espectroscópicas adequadas. Alguns compostos tiveram sua afinidade por H3R e H4R determinada em ensaios de binding competitivo com [3H]-histamina e atividade funcional avaliada por ensaios de ativação da proteína Gαi. O composto M1A1 pode ser destacado, demonstrando alta afinidade por H4R (pKi 7,1) com seletividade sobre H3R (pKi < 5,0), e atividade agonista parcial. Já os compostos B1A1, D2A6 e R1A1 não tiveram afinidade apreciável por nenhum dos receptores. Concluiu-se que, no geral, as modificações realizadas prejudicaram a afinidade dos compostos pelos receptores, embora muitos compostos ainda precisem ser avaliados futuramente.
Histamine is a chemical mediator that acts through 4 different G-protein-coupled receptors (H1, H2, H3 e H4). The H3 receptor (H3R) is predominantly found in the central nervous system (CNS), and it has function as auto-receptor, modulating the liberation of histamine on histaminergic neurons and as hetero-receptor, modulating the liberation of other neurotransmitters. Nowadays, the pitolisant is the only drug with activity for H3R that was approve for therapeutic use, due its antagonist activity, it is used to narcolepsy treatment. However, due its neurologic function, the H3R has several potentials as therapeutic target for CNS disorders, such as Alzheimer and Parkinson disease, schizophrenia and others. The H4 receptor was discover recently and it is mainly found on cells of immune system, thus drugs with antagonistic action on this receptor can be potential treatments for inflammatory diastases, such as asthma, inflammatory bowel diseases and other chronic inflammatory diseases. In light of the therapeutic potentials of H3R and H4R as pharmacological targets and the low number of available drugs with action in these receptors, it is evident the interest on search of new ligands. Our group is working on designing of these ligands, with promising result of the LINS01 series, some compounds of this series showed nanomolar affinity and efficacy on asthma and memory animal models. The main aim of this work was evaluate the influence of modifications on the aromatic and basic regions on the affinity for H3R and H4R. Thus, it was designed compounds containing the groups 2,3-hydroxybenzofurans, benzofurans, benzofuranyl amide, benzylurea and aniline in the lipophilic arbitrary region and piperazines, homopiperazines and ethylenediame groups on basic region, considering the pharmacophoric characteristics for interactions with the target. The compounds have been obtained using classic methodologies with 8-91% yield, the characterization is performed using adequate spectroscopic techniques. Some compounds had their affinity determined by competitive binding with [3H]-histamine and functional activity evaluated by activation of Gαi protein assay. The compounds M1A1 can be highlighted, demonstrating high affinity for H4R (pKi 7,1) with selective activity on H3R, and as partial agonist. The compounds B1A1, D2A6 and R1A1 did not have appreciable affinity by none of receptors. At this time, it is possible to conclude that the modifications decreased the affinities of the compounds for the receptors, although several compounds need to be evaluated in the future.
Histamine is a chemical mediator that acts through 4 different G-protein-coupled receptors (H1, H2, H3 e H4). The H3 receptor (H3R) is predominantly found in the central nervous system (CNS), and it has function as auto-receptor, modulating the liberation of histamine on histaminergic neurons and as hetero-receptor, modulating the liberation of other neurotransmitters. Nowadays, the pitolisant is the only drug with activity for H3R that was approve for therapeutic use, due its antagonist activity, it is used to narcolepsy treatment. However, due its neurologic function, the H3R has several potentials as therapeutic target for CNS disorders, such as Alzheimer and Parkinson disease, schizophrenia and others. The H4 receptor was discover recently and it is mainly found on cells of immune system, thus drugs with antagonistic action on this receptor can be potential treatments for inflammatory diastases, such as asthma, inflammatory bowel diseases and other chronic inflammatory diseases. In light of the therapeutic potentials of H3R and H4R as pharmacological targets and the low number of available drugs with action in these receptors, it is evident the interest on search of new ligands. Our group is working on designing of these ligands, with promising result of the LINS01 series, some compounds of this series showed nanomolar affinity and efficacy on asthma and memory animal models. The main aim of this work was evaluate the influence of modifications on the aromatic and basic regions on the affinity for H3R and H4R. Thus, it was designed compounds containing the groups 2,3-hydroxybenzofurans, benzofurans, benzofuranyl amide, benzylurea and aniline in the lipophilic arbitrary region and piperazines, homopiperazines and ethylenediame groups on basic region, considering the pharmacophoric characteristics for interactions with the target. The compounds have been obtained using classic methodologies with 8-91% yield, the characterization is performed using adequate spectroscopic techniques. Some compounds had their affinity determined by competitive binding with [3H]-histamine and functional activity evaluated by activation of Gαi protein assay. The compounds M1A1 can be highlighted, demonstrating high affinity for H4R (pKi 7,1) with selective activity on H3R, and as partial agonist. The compounds B1A1, D2A6 and R1A1 did not have appreciable affinity by none of receptors. At this time, it is possible to conclude that the modifications decreased the affinities of the compounds for the receptors, although several compounds need to be evaluated in the future.