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Drug Design and Development for Dementia, Epilepsy, and Other Neurological...
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Drug Design and Development for Dementia, Epilepsy, and Other Neurological Disorder Diseases

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 December 2024) | Viewed by 7934

Special Issue Editors

Dr. Junke Song

E-Mail Website
Guest Editor
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Interests: neuropharmacology; neurological disorders; stroke; Alzheimer's disease; Parkinson’s disease
Prof. Dr. Xiaobin Pang

E-Mail Website
Guest Editor
School of Pharmacy, Henan University, Kaifeng 475004, China
Interests: neuropharmacology; dementia; epilepsy; Alzheimer's disease; Parkinson’s disease; stroke; immunopharmacology
Dr. Yangyang He

E-Mail Website
Guest Editor
School of Pharmacy, Henan University, Kaifeng 475004, China
Interests: drug target identification and validation; cardiovascular and cerebrovascular diseases; neuropharmacology; Alzheimer's disease; Parkinson’s disease

Special Issue Information

Dear Colleagues,

Dementia, epilepsy, and other neurological disorder diseases continue to pose significant challenges to healthcare systems worldwide. The complex nature of these diseases demands multidisciplinary efforts to discover novel therapeutic strategies that can ameliorate symptoms, slow progression, and ultimately enhance the quality of life for affected individuals. In this context, the search for effective drugs and interventions is of paramount importance.

This Special Issue aims to advance our understanding of innovative approaches in the field of drug design and development for a spectrum of neurological disorders, including dementia, epilepsy, and related conditions. We welcome contributions encompassing a wide range of topics, including but not limited to:

  1. Target identification and validation: Insights into novel molecular targets implicated in neurological disorders and their validation as potential drug targets.
  2. Biological screening: High-throughput screening and in vitro assays to identify compounds with potential therapeutic effects.
  3. Preclinical studies: In vivo experimentation, animal models, and pharmacokinetic studies to evaluate drug candidates' efficacy and safety profiles.
  4. Mechanistic insights: Investigations into the mechanisms of action of potential drug candidates and their impact on neurological pathways.

We invite researchers from diverse backgrounds to contribute original research articles, reviews, and short communications that provide valuable insights into the drug design and development landscape for neurological disorders. By facilitating the exchange of knowledge and innovative ideas, this Special Issue aspires to accelerate progress in this critical field of research.

Dr. Junke Song
Prof. Dr. Xiaobin Pang
Dr. Yangyang He
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurological disorders diseases
  • dementia
  • epilepsy
  • neurodegenerative diseases
  • target identification and validation
  • biological screening
  • preclinical studies
  • mechanistic insights

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Published Papers (5 papers)

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Research

19 pages, 2233 KiB  
Article
Structure–Activity Relationship Studies in a Series of 2-Aryloxy-N-(pyrimidin-5-yl)acetamide Inhibitors of SLACK Potassium Channels
by Nigam M. Mishra, Brittany D. Spitznagel, Yu Du, Yasmeen K. Mohamed, Ying Qin, C. David Weaver and Kyle A. Emmitte
Molecules 2024, 29(23), 5494; https://doi.org/10.3390/molecules29235494 - 21 Nov 2024
Viewed by 1046
Abstract
Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare, serious, and pharmacoresistant epileptic disorder often linked to gain-of-function mutations in the KCNT1 gene. KCNT1 encodes the sodium-activated potassium channel known as SLACK, making small molecule inhibitors of SLACK channels a compelling [...] Read more.
Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare, serious, and pharmacoresistant epileptic disorder often linked to gain-of-function mutations in the KCNT1 gene. KCNT1 encodes the sodium-activated potassium channel known as SLACK, making small molecule inhibitors of SLACK channels a compelling approach to the treatment of EIMFS and other epilepsies associated with KCNT1 mutations. In this manuscript, we describe a hit optimization effort executed within a series of 2-aryloxy-N-(pyrimidin-5-yl)acetamides that were identified via a high-throughput screen. We systematically prepared analogs in four distinct regions of the scaffold and evaluated their functional activity in a whole-cell, automated patch clamp (APC) assay to establish structure-activity relationships for wild-type (WT) SLACK inhibition. Two selected analogs were also profiled for selectivity versus other members of the Slo family of potassium channels, of which SLACK is a member, and versus a panel of structurally diverse ion channels. The same two analogs were evaluated for activity versus the WT mouse channel as well as two clinically relevant mutant human channels. Full article
(This article belongs to the Special Issue Drug Design and Development for Dementia, Epilepsy, and Other Neurological Disorder Diseases)
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18 pages, 5449 KiB  
Article
Formononetin Exerts Neuroprotection in Parkinson’s Disease via the Activation of the Nrf2 Signaling Pathway
by Xiaotong Wang, Nianxin Kang, Ying Liu and Guojie Xu
Molecules 2024, 29(22), 5364; https://doi.org/10.3390/molecules29225364 - 14 Nov 2024
Cited by 3 | Viewed by 1405
Abstract
Parkinson’s disease (PD) is a prevalent neurodegenerative disease for which no effective treatment currently exists. In this study, we identified formononetin (FMN), a neuroprotective component found in herbal medicines such as Astragalus membranaceus and Glycyrrhiza uralensis, as a potential agent targeting multiple [...] Read more.
Parkinson’s disease (PD) is a prevalent neurodegenerative disease for which no effective treatment currently exists. In this study, we identified formononetin (FMN), a neuroprotective component found in herbal medicines such as Astragalus membranaceus and Glycyrrhiza uralensis, as a potential agent targeting multiple pathways involved in PD. To investigate the anti-PD effects of FMN, we employed Caenorhabditis elegans (C. elegans) PD models, specifically the transgenic strain NL5901 and the MPP(+)-induced strain BZ555, to investigate the effects of FMN on the key pathological features of PD, including dyskinesia, dopamine neuron damage, and reactive oxygen species (ROS) accumulation. The MPP(+)-induced SH-SY5Y cell PD model was utilized to evaluate the effects of FMN on cell viability, ROS accumulation, and mitochondrial dysfunction. The signaling pathway induced by FMN was analyzed using transcriptomic techniques and subsequently validated in vitro. Our results indicate that FMN significantly reduced ROS accumulation and improved both dopaminergic neuron vitality and dyskinesia in the C. elegans PD models. In the cell PD model, FMN significantly reduced ROS accumulation and enhanced mitochondrial membrane potential (MMP) and cell viability. A transcriptomic analysis suggested that the effects of FMN are associated with Nrf2 activation. Furthermore, ML385, a specific Nrf2 inhibitor, blocked the beneficial effects of FMN in vitro, indicating that FMN ameliorates dyskinesia and protects dopaminergic neurons through Nrf2 signaling pathway activation. In addition, the effects of FMN on ameliorating dyskinesia and protecting dopamine neurons were comparable to those of the Nrf2 agonist of sulforaphane (SFN) in vivo. The results of this study confirm that FMN exerts significant anti-PD effects primarily through the Nrf2 signaling pathway. These findings provide crucial insights for the development of anti-PD therapies. Full article
(This article belongs to the Special Issue Drug Design and Development for Dementia, Epilepsy, and Other Neurological Disorder Diseases)
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19 pages, 3250 KiB  
Article
Inhibition of Monoamine Oxidases by Pyridazinobenzylpiperidine Derivatives
by Jong Min Oh, Yaren Nur Zenni, Zeynep Özdemir, Sunil Kumar, Semanur Kılıç, Mevlüt Akdağ, Azime Berna Özçelik, Hoon Kim and Bijo Mathew
Molecules 2024, 29(13), 3097; https://doi.org/10.3390/molecules29133097 - 28 Jun 2024
Viewed by 1248
Abstract
Monoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase [...] Read more.
Monoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase the effectiveness and safety of treating Parkinson’s disease, new scaffolds for reversible MAO-B inhibitors are being developed. A total of 24 pyridazinobenzylpiperidine derivatives were synthesized and evaluated for MAO. Most of the compounds showed a higher inhibition of MAO-B than of MAO-A. Compound S5 most potently inhibited MAO-B with an IC50 value of 0.203 μM, followed by S16 (IC50 = 0.979 μM). In contrast, all compounds showed weak MAO-A inhibition. Among them, S15 most potently inhibited MAO-A with an IC50 value of 3.691 μM, followed by S5 (IC50 = 3.857 μM). Compound S5 had the highest selectivity index (SI) value of 19.04 for MAO-B compared with MAO-A. Compound S5 (3-Cl) showed greater MAO-B inhibition than the other derivatives with substituents of -Cl > -OCH3 > -F > -CN > -CH3 > -Br at the 3-position. However, the 2- and 4-position showed low MAO-B inhibition, except S16 (2-CN). In addition, compounds containing two or more substituents exhibited low MAO-B inhibition. In the kinetic study, the Ki values of S5 and S16 for MAO-B were 0.155 ± 0.050 and 0.721 ± 0.074 μM, respectively, with competitive reversible-type inhibition. Additionally, in the PAMPA, both lead compounds demonstrated blood–brain barrier penetration. Furthermore, stability was demonstrated by the 2V5Z-S5 complex by pi–pi stacking with Tyr398 and Tyr326. These results suggest that S5 and S16 are potent, reversible, selective MAO-B inhibitors that can be used as potential agents for the treatment of neurological disorders. Full article
(This article belongs to the Special Issue Drug Design and Development for Dementia, Epilepsy, and Other Neurological Disorder Diseases)
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19 pages, 2148 KiB  
Article
Structure–Activity Relationship Studies in a Series of Xanthine Inhibitors of SLACK Potassium Channels
by Alshaima’a M. Qunies, Brittany D. Spitznagel, Yu Du, Paul K. Peprah, Yasmeen K. Mohamed, C. David Weaver and Kyle A. Emmitte
Molecules 2024, 29(11), 2437; https://doi.org/10.3390/molecules29112437 - 22 May 2024
Cited by 3 | Viewed by 1611
Abstract
Gain-of-function mutations in the KCNT1 gene, which encodes the sodium-activated potassium channel known as SLACK, are associated with the rare but devastating developmental and epileptic encephalopathy known as epilepsy of infancy with migrating focal seizures (EIMFS). The design of small molecule inhibitors of [...] Read more.
Gain-of-function mutations in the KCNT1 gene, which encodes the sodium-activated potassium channel known as SLACK, are associated with the rare but devastating developmental and epileptic encephalopathy known as epilepsy of infancy with migrating focal seizures (EIMFS). The design of small molecule inhibitors of SLACK channels represents a potential therapeutic approach to the treatment of EIMFS, other childhood epilepsies, and developmental disorders. Herein, we describe a hit optimization effort centered on a xanthine SLACK inhibitor (8) discovered via a high-throughput screen. Across three distinct regions of the chemotype, we synthesized 58 new analogs and tested each one in a whole-cell automated patch-clamp assay to develop structure–activity relationships for inhibition of SLACK channels. We further evaluated selected analogs for their selectivity versus a variety of other ion channels and for their activity versus clinically relevant SLACK mutants. Selectivity within the series was quite good, including versus hERG. Analog 80 (VU0948578) was a potent inhibitor of WT, A934T, and G288S SLACK, with IC50 values between 0.59 and 0.71 µM across these variants. VU0948578 represents a useful in vitro tool compound from a chemotype that is distinct from previously reported small molecule inhibitors of SLACK channels. Full article
(This article belongs to the Special Issue Drug Design and Development for Dementia, Epilepsy, and Other Neurological Disorder Diseases)
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18 pages, 6216 KiB  
Article
Network Proximity Analysis Deciphers the Pharmacological Mechanism of Osthole against D-Galactose Induced Cognitive Disorder in Rats
by Xue Wang, Xiaomei Fu, Xiurong Luo, Yiyi Lai, Chuipu Cai, Yanfang Liao, Zhao Dai, Shuhuan Fang and Jiansong Fang
Molecules 2024, 29(1), 21; https://doi.org/10.3390/molecules29010021 - 19 Dec 2023
Cited by 3 | Viewed by 1719
Abstract
Osthole, a natural coumarin found in various medicinal plants, has been previously reported to have neuroprotective effects. However, the specific mechanism by which Osthole alleviates dysmnesia associated with Alzheimer’s disease (AD) remains unclear. This study aimed to investigate the neuroprotective properties of Osthole [...] Read more.
Osthole, a natural coumarin found in various medicinal plants, has been previously reported to have neuroprotective effects. However, the specific mechanism by which Osthole alleviates dysmnesia associated with Alzheimer’s disease (AD) remains unclear. This study aimed to investigate the neuroprotective properties of Osthole against cognitive impairment in rats induced by D-galactose and elucidate its pharmacological mechanism. The rat model was established by subcutaneously injecting D-galactose at a dose of 150 mg/kg/day for 56 days. The effect of Osthole on cognitive impairment was evaluated by behavior and biochemical analysis. Subsequently, a combination of in silico prediction and experimental validation was performed to verify the network-based predictions, using western blot, Nissl staining, and immunofluorescence. The results demonstrate that Osthole could improve memory dysfunction induced by D-galactose in Sprague Dawley male rats. A network proximity-based approach and integrated pathways analysis highlight two key AD-related pathological processes that may be regulated by Osthole, including neuronal apoptosis, i.e., neuroinflammation. Among them, the pro-apoptotic markers (Bax), anti-apoptotic protein (Bcl-2), the microgliosis (Iba-1), Astro-cytosis (GFAP), and inflammatory cytokines (TNF-R1) were evaluated in both hippocampus and cortex. The results indicated that Osthole significantly ameliorated neuronal apoptosis and neuroinflammation in D-galactose-induced cognitive impairment rats. In conclusion, this study sheds light on the pharmacological mechanism of Osthole in mitigating D-galactose-induced memory impairment and identifies Osthole as a potential drug candidate for AD treatment, targeting multiple signaling pathways through network proximity and integrated pathways analysis. Full article
(This article belongs to the Special Issue Drug Design and Development for Dementia, Epilepsy, and Other Neurological Disorder Diseases)
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