RESUMO
Histamine is involved in several central nervous system processes including cognition. In the last years, H3 receptor (H3 R) antagonists have been widely explored for their potential on dementias and other cognitive dysfunctions, and the cooperative role between histamine and acetylcholine neurotransmissions on cognitive processes is widely known in literature. This motivated us to assess the potential of 1-[(2,3-dihydrobenzofuran-1-yl)methyl]piperazines (LINS01 compounds) as inhibitors of cholinesterases, and thus this work presents the inhibitory effect of such compounds against acetyl (AChE) and butyrylcholinesterase. A set of 16 selected compounds were evaluated, being compounds 2d and 2e the most potent inhibitors of both cholinesterases (IC50 13.2-33.9 µM) by competitive mechanism, as indicated by the kinetic assays. Molecular docking simulations suggested that the allylpiperazine and dihydrobenzofuran motifs present in these compounds are important to perform π-interactions with key tryptophan residues from the enzymes, increasing their affinity for both H3 R and cholinesterases. Metric analysis support that compound 2d (LINS01022) should be highlighted due to its balanced lipophilicity (ClogP 2.35) and efficiency (LE 0.32) as AChE inhibitor. The results add important information to future design of dual H3 R-cholinesterases ligands.
Assuntos
Doença de Alzheimer , Receptores Histamínicos H3 , Acetilcolina , Acetilcolinesterase/metabolismo , Benzofuranos/química , Benzofuranos/farmacologia , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Histamina , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Piperazinas/química , Piperazinas/farmacologia , Receptores Histamínicos H3/química , Relação Estrutura-Atividade , TriptofanoRESUMO
The role of histamine and acetylcholine in cognitive functions suggests that compounds able to increase both histaminergic and cholinergic neurotransmissions in the brain should be considered as promising therapeutic options. For this purpose, dual inhibitors of histamine H3 receptors (H3 R) and cholinesterases (ChEs) have been designed and assessed. In this context, this paper reviews the strategies used to obtain dual H3 R/ChEs ligands using multitarget design approaches. Hybrid compounds designed by linking tacrine or flavonoid motifs to H3 R antagonists were obtained with high affinity for both targets, and compounds designed by merging the H3 R antagonist pharmacophore with known anticholinesterase molecules were also reported. These reports strongly suggest that key modifications in the lipophilic region (including a second basic group) seem to be a strategy to reach novel compounds, allied with longer linker groups to a basic region. Some compounds have already demonstrated efficacy in memory models, although the pharmacokinetic and toxicity profile should be considered when designing further compounds. In conclusion, the key features to be considered when designing novel H3 R/ChEs inhibitors with improved pharmacological profile were herein summarized.
Assuntos
Colinesterases/química , Ligantes , Receptores Histamínicos H3/química , Sítios de Ligação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/uso terapêutico , Colinesterases/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/patologia , Desenho de Fármacos , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/metabolismo , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Receptores Histamínicos H3/metabolismoRESUMO
Histamine is a transmitter that activates the four receptors H1 R to H4 R. The H3 R is found in the nervous system as an autoreceptor and heteroreceptor, and controls the release of neurotransmitters, making it a potential drug target for neuropsychiatric conditions. We have previously reported that the 1-(2,3-dihydro-1-benzofuran-2-yl)methylpiperazines (LINS01 compounds) have the selectivity for the H3 R over the H4 R. Here, we describe their pharmacological properties at the human H1 R and H2 R in parallel with the H3 R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays. Eight of the nine LINS01 compounds inhibited H3 R-induced histamine responses, but no inhibition of H2 R-induced responses was seen. Three compounds were weakly able to inhibit H1 R-induced responses. No agonist responses were seen to any of the compounds at any receptor. SAR analysis shows that the N-methyl group improves H3 R affinity while the N-phenyl group is detrimental. The methoxy derivative, LINS01009, had the highest affinity.
Assuntos
Piperazinas/química , Receptores Histamínicos H1/química , Receptores Histamínicos H2/química , Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/metabolismo , Humanos , Cinética , Ligantes , Piperazinas/síntese química , Piperazinas/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/metabolismo , Receptores Histamínicos H3/metabolismo , Relação Estrutura-AtividadeRESUMO
Non-reinforced retrieval induces memory extinction, a phenomenon characterized by a decrease in the intensity of the learned response. This attribute has been used to develop extinction-based therapies to treat anxiety and post-traumatic stress disorders. Histamine modulates memory and anxiety but its role on fear extinction has not yet been evaluated. Therefore, using male Wistar rats, we determined the effect of the intra-hippocampal administration of different histaminergic agents on the extinction of step-down inhibitory avoidance (IA), a form of aversive learning. We found that intra-CA1 infusion of histamine immediately after non-reinforced retrieval facilitated consolidation of IA extinction in a dose-dependent manner. This facilitation was mimicked by the histamine N-methyltransferase inhibitor SKF91488 and the H2 receptor agonist dimaprit, reversed by the H2 receptor antagonist ranitidine, and unaffected by the H1 antagonist pyrilamine, the H3 antagonist thioperamide and the antagonist at the NMDA receptor (NMDAR) polyamine-binding site ifenprodil. Neither the H1 agonist 2-2-pyridylethylamine nor the NMDAR polyamine-binding site agonist spermidine affected the consolidation of extinction while the H3 receptor agonist imetit hampered it. Extinction induced the phosphorylation of ERK1 in dorsal CA1 while intra-CA1 infusion of the MEK inhibitor U0126 blocked extinction of the avoidance response. The extinction-induced phosphorylation of ERK1 was enhanced by histamine and dimaprit and blocked by ranitidine administered to dorsal CA1 after non-reinforced retrieval. Taken together, our data indicate that the hippocampal histaminergic system modulates the consolidation of fear extinction through a mechanism involving the H2-dependent activation of ERK signalling.