Pharmaceuticals, Год журнала: 2024, Номер 17(5), С. 639 - 639
Опубликована: Май 15, 2024
Neurodegenerative disorders (NDs) include a range of chronic conditions characterized by progressive neuronal loss, leading to cognitive, motor, and behavioral impairments. Common examples Alzheimer's disease (AD) Parkinson's (PD). The global prevalence NDs is on the rise, imposing significant economic social burdens. Despite extensive research, mechanisms underlying remain incompletely understood, hampering development effective treatments. Excitotoxicity, particularly glutamate-mediated excitotoxicity, key pathological process implicated in NDs. Targeting N-methyl-D-aspartate (NMDA) receptor, which plays central role holds therapeutic promise. However, challenges, such as blood-brain barrier penetration adverse effects, extrapyramidal have hindered success many NMDA receptor antagonists clinical trials. This review explores molecular antagonists, emphasizing their structure, function, types, future prospects treating research competitive noncompetitive quest for treatments still faces hurdles. partly because same that necessitates blockage under also responsible normal physiological function receptors. Allosteric modulation receptors presents potential alternative, with GluN2B subunit emerging attractive target due its enrichment presynaptic extrasynaptic receptors, are major contributors excitotoxic-induced cell death. low side-effect profiles, selective like ifenprodil radiprodil encountered obstacles poor bioavailability Moreover, selectivity these often relative, they been shown bind other GluN2 subunits, albeit minimally. Recent advancements developing phenanthroic naphthoic acid derivatives offer promise enhanced GluN2B, GluN2A or GluN2C/GluN2D improved pharmacodynamic properties. Additional challenges antagonist conflicting preclinical results, well complexity neurodegenerative poorly defined subtypes. Although multifunctional agents targeting multiple degenerative processes being explored, data limited. Designing antagonists/modulators polycyclic moieties multitarget properties would be addressing disorders. understanding structure coupled collaborative efforts drug design, imperative realizing antagonists/modulators.
Язык: Английский
Процитировано
23
European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 265, С. 116123 - 116123
Опубликована: Янв. 3, 2024
Язык: Английский
Процитировано
21
European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 275, С. 116569 - 116569
Опубликована: Июнь 5, 2024
Язык: Английский
Процитировано
17
European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 251, С. 115253 - 115253
Опубликована: Март 10, 2023
Язык: Английский
Процитировано
22
Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2023, Номер 38(1)
Опубликована: Янв. 23, 2023
A series of novel quinoline-O-carbamate derivatives was rationally designed for treating Alzheimer's disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated AChE/BuChE inhibition anti-inflammatory property. in vitro activities showed that compound 3f a reversible dual eeAChE/eqBuChE inhibitor with IC50 values 1.3 µM 0.81 µM, respectively. Moreover, displayed good property decreasing the production IL-6, IL-1β NO. In addition, presented significant neuroprotective effect on Aβ25-35-induced PC12 cell injury. Furthermore, stabilities artificial gastrointestinal fluids, liver microsomes plasma. could improve AlCl3-induced zebrafish AD model increasing level ACh. Therefore, promising multifunctional agent treatment AD.
Язык: Английский
Процитировано
21
Frontiers in Aging Neuroscience, Год журнала: 2023, Номер 15
Опубликована: Март 3, 2023
With the development trend of an aging society, Alzheimer’s disease (AD) has become urgent problem in field medicine worldwide. Cognitive impairment AD patients leads to a decline ability perform daily living and abnormalities behavior personality, causing abnormal psychiatric symptoms, which seriously affect life patients. Currently, mainly drug therapy is used for clinic, but large proportion will experience efficacy not working, even some drugs bring severe sleep disorders. Acupuncture, with its unique concept treatment method, been validated through number experiments proved reliability acupuncture AD. Many advances have made study neurobiological mechanisms AD, further demonstrating good advantages This review first summarizes pathogenesis then illustrates research progress includes effect on changes biochemical indicators vivo specific mechanism action exert therapeutic effect. Changes relevant similarly validate effectiveness treatment. The clinical mechanistic studies are intensified fit need social development. It believed that achieve new achievements as progresses.
Язык: Английский
Процитировано
21
Chemical Physics Impact, Год журнала: 2023, Номер 7, С. 100361 - 100361
Опубликована: Ноя. 14, 2023
A series of 32 molecules derived from 7-prenyloxy-2,3-dihydroflavanone and 5-hydroxy-7-prenyloxy-2,3-dihydro-flavanone possessing an inhibitory activity against the Acetylcholinesterase (AChE) enzyme were studied using structure-activity (QSAR) investigations. Electronic descriptors calculated Gaussian software DFT method at B3YP/6-31G(d, p) level. In addition, constitutional, physicochemical, topological Chem3D software. The best model obtained by multiple linear regression (MLR) was subjected to external internal statistical validations. What is more, applicability domain (ad) has been defined for built Williams plot. We have designed new molecular structures similar basis giving dataset their predicted model. Then, docking used predict affinity between newly inhibitors candidates AChE protein. This study completed dynamic simulation (MDs) stability formed complexes, RMSD RMSF plots complexes analyzed.
Язык: Английский
Процитировано
21
Amino Acids, Год журнала: 2023, Номер 55(12), С. 1765 - 1774
Опубликована: Март 20, 2023
Язык: Английский
Процитировано
19
Journal of Molecular Structure, Год журнала: 2024, Номер 1306, С. 137841 - 137841
Опубликована: Фев. 22, 2024
Язык: Английский
Процитировано
9
Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2024, Номер 39(1)
Опубликована: Фев. 16, 2024
Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer's disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives evaluated their activities against cholinesterases neuroinflammation. The optimal compound 7p exhibited balanced BuChE inhibitory activity (eqBuChE IC50 = 4.68 nM; huBuChE 9.12 nM) anti-neuroinflammatory (NO inhibition 28.82% at 10 μM, comparable to hydrocortisone). Enzyme kinetic docking studies confirmed was a mix-type inhibitor. Additionally, displayed favourable drug-likeness properties in silico prediction, high BBB permeability the PAMPA-BBB assay. Compound had good safety vivo verified by an acute toxicity assay (LD50 > 1000 mg/kg). Most importantly, effectively mitigated cognitive memory impairments scopolamine-induced mouse model, showing effects Rivastigmine. Therefore, envisioned that could serve lead treating AD.
Язык: Английский
Процитировано
8