Search for multifunctional agents against Alzheimer’s disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives

Jończyk, Jakub; Lodarski, Krzysztof; Staszewski, Marek; Godyń, Justyna; Zaręba, Paula; Soukup, Ondřej; Janočková, Jana; Korábečný, Jan; Sałat, Kinga; Malikowska‐Racia, Natalia; Hebda, Michalina; Szałaj, Natalia; Filipek, Barbara; Walczyński, Krzysztof; Malawska, Barbara; Bajda, Marek

doi:10.1016/j.bioorg.2019.103084

Cited by 14 publications

(5 citation statements)

References 42 publications

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“…This effect has two consequences: it increases the availability of the electron donor present on the pyridine nitrogen atom (increasing its basicity; DMAP p K a = 9.2 vs pyridine p K a = 5.2) and, at the same time, reduces the availability of the electron donor present on the nitrogen atom 1 of the piperazine system (decreasing its basicity; 1,4-dimethylpiperazine p K a = 8.4). Considering that the literature describes ligands that can be found in the active site of a protein target in doubly protonated state, , we have conducted the docking of the compounds containing the piperazine moiety, considering them in state 4 of Figure .…”

Section: Results and Discussionmentioning

confidence: 99%

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H₃ and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Szczepańska

Podlewska

Dichiara

et al. 2021

ACS Chem. Neurosci.

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In an attempt to extend recent studies showing that some clinically evaluated histamine H 3 receptor (H 3 R) antagonists possess nanomolar affinity at sigma-1 receptors (σ 1 R), we selected 20 representative structures among our previously reported H 3 R ligands to investigate their affinity at σRs. Most of the tested compounds interact with both sigma receptors to different degrees. However, only six of them showed higher affinity toward σ 1 R than σ 2 R with the highest binding preference to σ 1 R for compounds 5 , 11 , and 12 . Moreover, all these ligands share a common structural feature: the piperidine moiety as the fundamental part of the molecule. It is most likely a critical structural element for dual H 3 /σ 1 receptor activity as can be seen by comparing the data for compounds 4 and 5 (hH 3 R K i = 3.17 and 7.70 nM, σ 1 R K i = 1531 and 3.64 nM, respectively), where piperidine is replaced by piperazine. We identified the putative protein–ligand interactions responsible for their high affinity using molecular modeling techniques and selected compounds 5 and 11 as lead structures for further evaluation. Interestingly, both ligands turned out to be high-affinity histamine H 3 and σ 1 receptor antagonists with negligible affinity at the other histamine receptor subtypes and promising antinociceptive activity in vivo . Considering that many literature data clearly indicate high preclinical efficacy of individual selective σ 1 or H 3 R ligands in various pain models, our research might be a breakthrough in the search for novel, dual-acting compounds that can improve existing pain therapies. Determining whether such ligands are more effective than single-selective drugs will be the subject of our future studies.

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Section: Results and Discussionmentioning

confidence: 99%

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H₃ and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Szczepańska

Podlewska

Dichiara

et al. 2021

ACS Chem. Neurosci.

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“…Recent work from Jonczyk et al. (2019) also reported non‐symmetrical bibasic compounds containing a piperazine moiety, being the compound 16 noteworthy due to best potency on H 3 R with micromolar affinity for AChE. This compound also proved to have positive effect on memory in a passive avoidance model test.…”

Section: Merging As Strategymentioning

confidence: 89%

“…The second piperidine from compound 15 possibly performs an interaction with Asp3.32 from H3R and a cation‐π interaction with the second tryptophan residue in the CAS region of AChE (Incerti et al., 2010). On the other hand, no interaction with Asp3.32 was observed to compound 16 , and π‐π interaction between the phenyl ring of the compound and tryptophan from the CAS region of AChE was observed (Jończyk et al., 2019).…”

Section: Merging As Strategymentioning

confidence: 99%

Histamine H₃ receptor and cholinesterases as synergistic targets for cognitive decline: Strategies to the rational design of multitarget ligands

2021

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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 H 3 receptors (H 3 R) and cholinesterases (ChEs) have been designed and assessed. In this context, this paper reviews the strategies used to obtain dual H 3 R/ChEs ligands using multitarget design approaches. Hybrid compounds designed by linking tacrine or flavonoid motifs to H 3 R antagonists were obtained with high affinity for both targets, and compounds designed by merging the H 3 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 H 3 R/ChEs inhibitors with improved pharmacological profile were herein summarized.

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“…Recently, the multi-target-directed ligands of histamine receptors gained a lot of attention [45,57,68,78,94,95] that led to development of multi-targeted ligands of H 3 R, serotonin receptors, as well as acetylcholinesterases (AChE and BuChE), for potential treatment of neurodegenerative diseases such as Alzheimer's disease. Jonczyk et al [68] identified multi-targeted piperazine derivatives to be blockers of AChE and BuChE as well as of hH 3 R. The ligands were bound to E 5.46 , as this was suggested to be a crucial interaction for H 3 R antagonistic activity, while the other interactions were with residues F163 ECL2 , Y 3.33 and Y 6.51 [68]. Lepailleur et al [49] performed ligand-based pharmacophore-guided virtual screening of CERMN chemical compound library (17,194 compounds) using six active H 3 R ligands with the purpose of designing dual targeting H 3 R/5-HT 4 R ligands.…”

Section: Multi-target H 3 R Ligandsmentioning

confidence: 99%

Molecular Modeling of Histamine Receptors—Recent Advances in Drug Discovery

Mehta

Filipek

2021

Molecules

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The recent developments of fast reliable docking, virtual screening and other algorithms gave rise to discovery of many novel ligands of histamine receptors that could be used for treatment of allergic inflammatory disorders, central nervous system pathologies, pain, cancer and obesity. Furthermore, the pharmacological profiles of ligands clearly indicate that these receptors may be considered as targets not only for selective but also for multi-target drugs that could be used for treatment of complex disorders such as Alzheimer’s disease. Therefore, analysis of protein-ligand recognition in the binding site of histamine receptors and also other molecular targets has become a valuable tool in drug design toolkit. This review covers the period 2014–2020 in the field of theoretical investigations of histamine receptors mostly based on molecular modeling as well as the experimental characterization of novel ligands of these receptors.

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Search for multifunctional agents against Alzheimer’s disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives

Cited by 14 publications

References 42 publications

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H₃ and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H₃ and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Histamine H₃ receptor and cholinesterases as synergistic targets for cognitive decline: Strategies to the rational design of multitarget ligands

Molecular Modeling of Histamine Receptors—Recent Advances in Drug Discovery

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Search for multifunctional agents against Alzheimer’s disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives

Cited by 14 publications

References 42 publications

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H3 and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H3 and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Histamine H3 receptor and cholinesterases as synergistic targets for cognitive decline: Strategies to the rational design of multitarget ligands

Molecular Modeling of Histamine Receptors—Recent Advances in Drug Discovery

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Product

Resources

About

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H₃ and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H₃ and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Histamine H₃ receptor and cholinesterases as synergistic targets for cognitive decline: Strategies to the rational design of multitarget ligands