Central nervous system agents in medicinal chemistry最新文献

Background: The gut-brain axis (GBA) is a bidirectional signaling channel that facilitates communication between the gastrointestinal tract and the brain. Recent research on the gut-brain axis demonstrates that this connection enables the brain to influence gut function, which in turn influences the brain and its cognitive functioning. It is well established that malfunctioning of this axis adversely affects both systems' ability to operate effectively.

Objective: Dysfunctions in the GBA have been associated with disorders of gut motility and permeability, intestinal inflammation, indigestion, constipation, diarrhea, IBS, and IBD, as well as neuropsychiatric and neurodegenerative disorders like depression, anxiety, schizophrenia, autism, Alzheimer's, and Parkinson's disease. Multiple research initiatives have shown that the gut microbiota, in particular, plays a crucial role in the GBA by participating in the regulation of a number of key neurochemicals that are known to have significant effects on the mental and physical well-being of an individual.

Methods: Several studies have investigated the relationship between neuropsychiatric disorders and imbalances or disturbances in the metabolism of neurochemicals, often leading to concomitant gastrointestinal issues and modifications in gut flora composition. The interaction between neurological diseases and gut microbiota has been a focal point within this research. The novel therapeutic interventions in neuropsychiatric conditions involving interventions such as probiotics, prebiotics, and dietary modifications are outlined in this review.

Results: The findings of multiple studies carried out on mice show that modulating and monitoring gut microbiota can help treat symptoms of such diseases, which raises the possibility of the use of probiotics, prebiotics, and even dietary changes as part of a new treatment strategy for neuropsychiatric disorders and their symptoms.

Conclusion: The bidirectional communication between the gut and the brain through the gut-brain axis has revealed profound implications for both gastrointestinal and neurological health. Malfunctions in this axis have been connected to a range of disorders affecting gut function as well as cognitive and neuropsychiatric well-being. The emerging understanding of the role of gut microbiota in regulating key neurochemicals opens up possibilities for novel treatment approaches for conditions like depression, anxiety, and neurodegenerative diseases.

Background: Overactivation of receptors that respond to excitatory neurotransmitters can result in various harmful outcomes, such as the inability to properly modulate calcium levels, generation of free radicals, initiation of the mitochondrial permeability transition, and subsequent secondary damage caused by excitotoxicity. A non-proteinogenic amino acid of tea, L-theanine, is structurally related to glutamate, the major stimulatory neurotransmitter in the brain. Previous reports have emphasised its ability to bind with glutamate receptors.

Objective: An in-depth understanding of the binding compatibility between ionotropic glutamate receptors and L-theanine is a compelling necessity.

Methods: In this molecular docking study, the antagonistic effect of L-theanine and its possible therapeutic benefit in GluR5 kainate receptor inhibition has been evaluated and compared to the familiar AMPA and kainite receptor antagonists, cyanoquinoxaline (CNQX) and dinitroquinoxaline (DNQX), using Molegro Virtual Docker 7.0.0.

Results: The capacity of L-theanine to cohere with the GluR5 receptor was revealed to be higher than that of glutamate, although it could not surpass the high binding tendency of competitive antagonists CNQX and DNQX. Nonetheless, the drug-likeness score and the blood-brain barrier traversing potential of L-theanine were higher than CNQX and DNQX.

Conclusion: The study provides an inference to the advantage of L-theanine, which can be a safe and effective alternative natural therapy for rescuing neuronal death due to excitotoxicity.

Stroke continues to be the main cause of motor disability worldwide. While rehabilitation has been promised to improve recovery after stroke, efficacy in clinical trials has been mixed. We need to understand the cortical recombination framework to understand how biomarkers for neurophysiological reorganized neurotechnologies alter network activity. Here, we summarize the principles of the movement network, including the current evidence of changes in the connections and function of encephalic regions, recovery from stroke and the therapeutic effects of rehabilitation. Overall, improvements or therapeutic effects in limb motor control following stroke are correlated with the effects of interhemispheric competition or compensatory models of the motor supplementary cortex. This review suggests that future research should focus on cross-regional communication and provide fundamental insights into further treatment and rehabilitation for post-stroke patients.

Alzheimer's disease (AD) is a relevant neurodegenerative disease worldwide. Its relevancy is mainly due to its high prevalence and high global burden. Metalloids have attracted attention as their serum levels seem to differ between affected patients and healthy individuals. On the other hand, atoms of some metalloids have been included in bioactive molecules, exerting some interesting effects, mainly due to their ameliorative effects in neurodegeneration. In this sense, boron-containing compounds (BCC) have been explored to regulate or prevent neurodegeneration. As an example, boric acid has been reported as a compound with antioxidant, anti-inflammatory and neurotrophic effects. Other natural BCCs have also shown amelioration of metabolic conditions often related to increased risk of neurodegenerative maladies. However, in recent years, additional organoboron compounds have been reported as active in several processes linked to neurodegeneration and especially attractive as regulators of the origin and progression of AD. In this mini-review, some data are collected suggesting that some natural BCC could be used as preventive agents, but also the potential of some BODIPYs as tools for diagnosis and some other BCC (particularly boronic acids and pinacol boronic esters) for acting as promising therapeutic agents for AD.

Background: Alzheimer's disease is a progressive neurodegenerative disorder for which no curative drugs are available and treatment available is just palliative.

Objectives: Current research focused on design of Tacrine-Flavone hybrids as multitargeted cholinesterase and monoamine oxidase B inhibitors.

Methods: A total of 10 Tacrine- Flavone hybrids were designed, synthesized and characterized. The in vitro neurotoxicity and hepatotoxicity of the synthesized compounds determined using SHSY5Y cell line and HEPG2 cell line. One most active compound (AF1) with least toxicity in in vitro studies was chosen for in vivo studies. Acute and subacute toxicity of the novel compound AF1 conducted on Wistar rats according to OECD guideline 423 and 407. The LD50 value of the novel compound calculated according to Finney's method using Probit analysis. Anti-Alzheimer's activity studies conducted on male Wistar rats. Behavioral studies conducted and AChE and MAO-B activity determined in rat brain.

Results and discussion: All the compounds exhibited good inhibitory effect on MAO B and AChE. The neurotoxicity studies of the active compound AF1 did not show toxicity up to 100μg. The hepatotoxicity study of the most active compound AF1, showed the compound to be safe up to 200μg. The LD 50 value of the novel compound after a single oral administration was found to be 64 mg/kg bodyweight in rats. Subacute toxicity studies did not show any remarkable toxicity in the vital organs up to 40 mg/kg. Activity studies showed comparable results with standard at 20 mg/kg.

Conclusion: The results showed that the novel Tacrine-Flavone hybrids are multitarget-directed ligands, which are safe and active compared to tacrine and can be a promising lead molecule for further study.

Background: Epilepsy is a neurological disorder, characterized by seizures accompanied by loss or disturbance of consciousness affecting various physical and mental functions. Current anticonvulsant drugs are effective in controlling seizures in about 70% of cases, but their use is often limited by side effects like ataxia, megaloblastic anemia, hepatic failure. In search for a novel anticovulsant drug with better efficacy and lower toxicity, a series of novel pyrimidine based semicarbazone were designed and evaluated for antiepileptic activity.

Methods: The test compounds were designed on the basis of four site binding hypothesis proposed for anticonvulsant activity. The chemical structures of the test compounds were elucidated using spectral (IR, 1H NMR, 13C NMR and MS) and elemental analysis. The minimal motor impairment activity was determined in mice using rotorod test. The maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models were employed for anticonvulsant evaluation.

Results: The results reveal that 76% of the compounds were active in the MES screening as compared to 53% of the compounds in the scPTZ test. Test compounds showed some MES selectivity displaying their effectiveness in generalized seizures of the tonic-clonic type. The molecular docking analysis of semicarbazone derivatives showed good ligand-receptor interactions with specially hydrogen bond interactions with ARG192, GLU270 and THR353 amino acid of receptor.

Conclusion: The present report confirms that pharmacophore model with four binding sites is crucial for anticonvulsant activity in the semicarbazones.

Thiazolidines are multifaceted molecules and exhibit varied types of biological activities, and also showed anticonvulsants and antidepressants activity. It is the diversified class of heterocyclic compounds. Thiazolidinediones (TZD) has been shown beneficial action in various CNS diseases. The significant mechanism of TZD-induced neuroprotection useful in prevention of microglial activation and cytokine that is responsible for inflammatory condition and chemokine expression. At the molecular level TZDs were also responsible to prevent the activation of pro-inflammatory transcription factors as well as promoting the anti-oxidant mechanisms in the injured CNS. Important SAR, molecular mechanism and potent biological activities with special references to central nervous system are discussed in this article. Various investigations suggest that this moiety pave the way for design and discovery of new drug candidates.

Background: Degradation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) is mainly catalysed by GABA aminotransferase (GABA-AT), excessive activity of which leads to convulsions. Inhibition of GABA-AT increases the concentration of GABA and can terminate the convulsions. Several studies have revealed that GABA analogues could be the outstanding scaffolds for the design of potent inhibitors of GABA-AT. The poor ability of GABA analogues to cross the blood-brain barrier (BBB), always produces low therapeutic index. However, Vigabatrin, a mechanism-based inhibitor of GABA-AT, is currently approved treatment of epilepsy, but it has harmful side effects, leaving a need for improved GABA-AT inactivators.

Experimental design: In our present in silico investigation, AutoDock 4.2,-based on Lamarckian genetic algorithm was employed for virtual screen of a compound library with 35 entries (Schiff's bases of GABA) in search for novel and selective inhibitors of GABA-AT.

Results: By means of flexible type of molecular docking, we proposed that these designed molecules could successfully bind into the active pocket of GABA-AT with good predicted affinities in comparison to standard vigabatrin. Among the designed analogues, HIG18, HIG28 and HIG30 showed significant binding free energy of -10.25, -9.88 and -9.31 kcal/mol with predicted inhibitory constant values of 0.03, 0.05 and 0.15 µM respectively.

Conclusion: Using ligand-based drug design, we proposed that electron withdrawing phenyl substituted heterocyclic imines of GABA could be considered as promising structures for synthesis and testing of new GABA-AT inhibitors from this class. We hypothesize that novel GABA analogues with an azomethine linkage incorporated with heterocyclic system can have increased affinity and more lipophilic character that would provide a probability of having less toxic effect in the therapy of convulsions.