QSAR Modeling of Histamine H3R Antagonists/inverse Agonists as Future Drugs for Neurodegenerative Diseases

Corrêa, Michelle Fidelis; Fernandes, João Paulo S.

doi:10.2174/1570159x15666170818100644

Cited by 7 publications

(4 citation statements)

References 40 publications

(59 reference statements)

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“…The lipophilic region can present several substituents including additional lipophilic or polar groups, or even a second basic group, while the substituents in the basic region are usually small lipophilic groups. These substituents drive the selectivity over other HA receptor subtypes, especially H 4 R (Corrêa et al, 2017(Corrêa et al, , 2021Correa & Fernandes, 2018).…”

Section: Opportunities On Dual -Targeting H R and Chesmentioning

confidence: 99%

“…Although HA is classically known for its involvement with allergic and inflammatory reactions, its role as neurotransmitter in the CNS in the regulation of feeding, sleep, hormonal homeostasis, and cognitive function has been focus of several researchers worldwide (Hu & Chen, 2017). HA acts through the activation of four different receptor subtypes (H 1 , H 2 , H 3, and H 4 receptors, H 1 R‐H 4 R) (Corrêa & Fernandes, 2015; Correa & Fernandes, 2018), which are part of the G‐protein coupled receptors (GPCRs) family, although G‐protein independent signaling pathways such as β‐arrestin (Pietraszewska‐Bogiel & Goedhart, 2019; Rosethorne & Charlton, 2011) and MAPK (Beermann et al., 2015; Rapanelli et al., 2016) pathways are frequently reported. All these receptors are expressed in the CNS, in neuronal and/or glial cells, playing roles in the neurotransmission of several neuronal pathways and brain processes.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Opportunities On Dual -Targeting H R and Chesmentioning

confidence: 99%

Section: Introductionmentioning

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 histamine H 3 receptor (H3R) is an inhibitory G protein-coupled receptor predominantly expressed in the CNS [112]. Activation of H3R inhibits the release of histamine as well as other neurotransmitters such as acetylcholine, norepinephrine, dopamine, and serotonin [113].…”

Section: Introductionmentioning

confidence: 99%

Failed, Interrupted, or Inconclusive Trials on Neuroprotective and Neuroregenerative Treatment Strategies in Multiple Sclerosis: Update 2015–2020

Huntemann

Rolfes

Pawlitzki

et al. 2021

Drugs

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In the recent past, a plethora of drugs have been approved for the treatment of multiple sclerosis (MS). These therapeutics are mainly confined to immunomodulatory or immunosuppressive strategies but do not sufficiently address remyelination and neuroprotection. However, several neuroregenerative agents have shown potential in pre-clinical research and entered Phase I to III clinical trials. Although none of these compounds have yet proceeded to approval, understanding the causes of failure can broaden our knowledge about neuroprotection and neuroregeneration in MS. Moreover, most of the investigated approaches are characterised by consistent mechanisms of action and proved convincing efficacy in animal studies. Therefore, learning from their failure will help us to enforce the translation of findings acquired in pre-clinical studies into clinical application. Here, we summarise trials on MS treatment published since 2015 that have either failed or were interrupted due to a lack of efficacy, adverse events, or for other reasons. We further outline the rationale underlying these drugs and analyse the background of failure to gather new insights into MS pathophysiology and optimise future study designs. For conciseness, this review focuses on agents promoting remyelination and medications with primarily neuroprotective properties or unconventional approaches. Failed clinical trials that pursue immunomodulation are presented in a separate article.

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“…The best candidates predicted by the LDA classification models were submitted to molecular docking and molecular dynamics. Also, the paper by Corrêa and Fernandes studied the QSAR works related to discovery of potential drugs related to histamine H3R receptor [ 36 ]. The H3R is an important target involved in several CNS disorders, such as narcolepsy, attention deficit hyperactivity disorder and schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Identification of Natural Compounds against Neurodegenerative Diseases Using In Silico Techniques

2018

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The aim of this study was to identify new potentially active compounds for three protein targets, tropomyosin receptor kinase A (TrkA), N-methyl-d-aspartate (NMDA) receptor, and leucine-rich repeat kinase 2 (LRRK2), that are related to various neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and neuropathic pain. We used a combination of machine learning methods including artificial neural networks and advanced multilinear techniques to develop quantitative structure–activity relationship (QSAR) models for all target proteins. The models were applied to screen more than 13,000 natural compounds from a public database to identify active molecules. The best candidate compounds were further confirmed by docking analysis and molecular dynamics simulations using the crystal structures of the proteins. Several compounds with novel scaffolds were predicted that could be used as the basis for development of novel drug inhibitors related to each target.

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QSAR Modeling of Histamine H3R Antagonists/inverse Agonists as Future Drugs for Neurodegenerative Diseases

Abstract: Although QSAR methods are valuable to design better H3R antagonists/inverse agonists, pharmacokinetics should also be considered in future models to ensure good CNS penetration.

Cited by 7 publications

References 40 publications

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

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

Failed, Interrupted, or Inconclusive Trials on Neuroprotective and Neuroregenerative Treatment Strategies in Multiple Sclerosis: Update 2015–2020

Identification of Natural Compounds against Neurodegenerative Diseases Using In Silico Techniques

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QSAR Modeling of Histamine H3R Antagonists/inverse Agonists as Future Drugs for Neurodegenerative Diseases

Abstract: Although QSAR methods are valuable to design better H3R antagonists/inverse agonists, pharmacokinetics should also be considered in future models to ensure good CNS penetration.

Cited by 7 publications

References 40 publications

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

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

Failed, Interrupted, or Inconclusive Trials on Neuroprotective and Neuroregenerative Treatment Strategies in Multiple Sclerosis: Update 2015–2020

Identification of Natural Compounds against Neurodegenerative Diseases Using In Silico Techniques

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Product

Resources

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

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