Central nervous system agents in medicinal chemistry最新文献

Background: In Alzheimer's Disease (AD), chemokines recruit pro-inflammatory mediators and increase the aggregation of both Aβ (amyloid-β) plaque and neurofibrillary tangles (NFTs). Chemokine receptor 5 (CCR5) has been demonstrated to be involved in neuroinflammation and neuroimmunology, where its inhibition was shown to enhance memory, plasticity and learning.

Objective: In this study, compounds that inhibit CCR5 obtained from the ChEMBL database were analysed, specifically for whether specific substructures and physicochemical properties are correlated to biological activity.

Methods: Clustering was first performed to group 1,237 compounds into 10 clusters based on the similarities of their structure. Then, molecular docking was performed on 10 compounds representative of each cluster. Lastly, the Spearman correlation was computed between physicochemical properties and biological activity.

Results: Results showed that potent CCR5 inhibitors tend to: (i) be larger in size (molecular weight of more than 500 g/mol), (ii) bind at the deep hydrophobic pocket, mostly through π-π stacking and (iii) have more than 1 aromatic ring. The larger size may aid in reaching the deep hydrophobic pocket. However, these requirements may lead to the violation of more than 1 Lipinski's Rule of 5.

Conclusion: Future studies should include analyses of the analogues or derivatives of the representative compounds to further expand on the findings here and establish the structure-activity relationship for CCR5 inhibition. This would aid in the development of new AD drugs since drug discovery and development of AD drugs are suffering from high attrition.

Background: NMDA receptors have a significant role in the development of opioid physical dependence. Evidence demonstrated that a drug of abuse enhances neuronal excitability in the Paraventricular Nucleus (PVT). The current research studied whether blocking NMDA receptors through the administration of MK801 in the PVT nucleus could affect the development of Morphine (Mor) dependence and hence the behavioral indices induced by morphine withdrawal in rats.

Methods: Male Wistar rats weighing 250-300 g were used. For induction of drug dependence, we injected Mor subcutaneously (s.c.) (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 hours for 7 days. Animals were divided into two groups in which the NMDA receptor antagonist, MK801 (20 mM in 0.1 ml), or its vehicle were applied into the PVT nucleus for 7 days before each Mor administration. On day 8, after injection of naloxone (Nal, 2.5 mg/kg, i.p.), withdrawal behaviors were checked for 25 min.

Results: The current results demonstrated that the blockade of the NMDA receptor in the PVT nucleus significantly increased withdrawal behaviors provoked by the application of Nal in morphinedependent (Mor-d) rats.

Conclusion: We concluded that the NMDA receptor in the PVT nucleus changes the development of Mor dependence.

Objective: Insomnia is a condition that causes sleep problems, and many people suffer from it. Patients with this disorder have difficulty with beginning or continuation of sleep, so they are exhausted all day long, and their performance reduces. This study was designed to assess the efficacy of capsules that contain tomato extract in patients with primary insomnia.

Methods: In this study, 70 patients with primary insomnia were assigned to 2 groups randomly: intervention and control. The intervention group used to take tomato capsules every night for 2 weeks, and the placebo one used to take placebo capsules every night for 2 weeks. All patients used to fill out Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI) questionnaires before and after the intervention. ISI and PSQI results were analyzed separately on SPSS software.

Results: A total of 70 patients (35 in the intervention group and 35 in the control group), including 50 females and 20 males, were studied. Female to male ratio and the rate of unemployment were significantly higher in the intervention group (in both cases P < 0.001), but there was no significant difference between the intervention and control groups in other characteristics (Age, marital status, weight, height, education; in all cases P > 0.05). At the end of the study, the amount of actual sleep had increased, and the delay in falling asleep decreased in both groups; the two groups at the end of the study were not significantly different in terms of these two variables (P > 0.05). The ISI score in both groups decreased significantly at the end of the study, and the PSQI score in both groups decreased significantly at the end of the study (In both cases, P < 0.05). The absolute value of ISI score change in the intervention group was significantly higher than the control group (P < 0.001); But the absolute value of PSQI score change was not significantly different between the two groups (P = 0.102). Most importantly, the improvement of both ISI and PSQI scores in the intervention group was significantly better than the control group (P > 0.05).

Conclusion: This study showed that tomato capsules have sleep-inducing effects, although there was no significant difference in the amount of actual sleep, and the delay in falling sleep in the intervention group compared to the control group.

Background: The most widespread signalling system in the brain is the cholinergic system, which plays a central role in the progress of Alzheimer's diseases (AD). Current AD treatment primarily targets the neuronal acetylcholinesterase (AChE) enzyme. The finding of AChE activity may play a vital role in optimizing assays for drug discovery of new AChE inhibiting agents. During in-vitro assay of AChE activity, the use of various organic solvents is imperative.

Objective: The present study is designed to evaluate the effect of different organic solvents on enzyme activity and enzyme kinetics.

Method: Organic solvents' AChE inhibitory potential (including enzyme kinetics: Vmax, Km and Kcat) was evaluated using substrate velocity curve by using non-linear reversion Michaelis-Menten kinetic function.

Results: DMSO was found to have the most potent AChE inhibitory effect, followed by acetonitrile and ethanol. The kinetic study revealed DMSO as a mixed inhibitory effect (competitive/noncompetitive manner), ethanol as non-competitive, and acetonitrile as a competitive inhibitor of the AChE enzyme. Methanol has shown a negligible impact on enzyme inhibition and kinetics, suggesting its suitability for the AChE assay.

Conclusion: We assume that our study results will help design the experimental protocols and support analyzing investigational outcomes while screening and biological evaluation of new molecules using methanol as solvent/cosolvent.

Introduction: The brain is the most complex organ in the human body, with a high and constant demand for inputs. Adequate nutrition is essential for the complete functioning of the brain, not only due to the energy supply, mainly from carbohydrates, but also due to the adequate supply of other macronutrients and micronutrients for the synthesis of neurotransmitters and protein components. Vitamins, minerals, and other components of the diet also constitute the so-called "neuro-nutrients".

Objective: It was to develop a systematic review to highlight key neuro-nutrients and clinical studies that direct strategies for adequate nutritional status.

Methods: The rules of the Systematic Review-PRISMA Platform were followed. The research was carried out from October 2021 to February 2022 and developed based on Scopus, PubMed, Science Direct, Scielo, and Google Scholar. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument.

Results: A total of 234 articles were found and 167 articles were evaluated in full, and 118 were included and evaluated in the present study. According to the GRADE instrument, most studies (>50%) followed a controlled clinical study model and had a good methodological design. The overall assessment resulted in 54 studies with a high risk of bias to the small sample size. The most important macronutrients in neuro-nutrition are phosphatidylserine and tryptophan. Micronutrients are methyl folate, vitamins B6 and B12, magnesium, arginine, choline, and niacin.

Conclusion: The areas of neurology and psychiatry have shown great advances regarding the deepening of knowledge in prophylaxis and pathophysiology, as well as in the treatment of established diseases. The recognition of the role of nutrition as an adjunct to these processes is currently growing. The search in scientific bases for neuro nutrients reveals a great growth of publications related to this theme. In the present text, some of these nutrients were explored to verify the current state of knowledge.

Objectives: Elaeocarpus ganitrus, a member of the Eleocarpaceae family, is valued in Hinduism and Ayurveda, and is frequently used as a remedy for a variety of illnesses. The plant is reputed to treat a number of stomach issues. The purpose of the study was to produce high-quality scientific data regarding gastroprotective behavior, docking experiments with cholinergic receptors, and HPTLC (with lupeol and ursolic acid). To develop the mechanism of herbal extracts, in vitro anticholinergic and antihistaminic activities were evaluated. Different leaf extracts were treated with various reagents to determine the presence of various metabolites. An examination of the histopathology was conducted to determine the full impact of the extract.

Methods: Methanolic extract was chosen for HPTLC investigations after extraction with various solvents. A mobile phase of toluene, ethylacetate, and formic acid (8:2:0.1) was chosen. Molecular docking was utilized to examine how ursolic acid and lupeol are bound to cholinergic receptors (M₃). Different extracts (aqueous and ethanolic) were tested for their ability to provide gastroprotection in Wistar rats at different doses (200 and 400 mg/kg).

Results: Phytochemical analysis of different extracts showed the presence of different primary and secondary metabolites. HPTLC data showed the presence of both standards. Docking studies exhibited very good interactions with the M₃ receptor. Pharmacological studies revealed that extract-treated groups significantly reduced the ulcer index in all of the models mentioned above. The histopathological analysis clearly supports the biochemical studies, which were conducted utilizing various doses and found to be effective in a dose-dependent manner. The in vitro analysis proved that the abovementioned extracts may act as antagonists of acetylcholine and histamine.

Conclusion: The data obtained would be valuable for the production of the monograph of the plant and conducting concept-related clinical studies in the future. More investigation is required since the gathered scientific data may lead to new research opportunities.

Introduction: Toxoplasmosis and narcotic drug addiction are endemic in various regions of Iran. These drugs can provide situations for infections by disrupting the immune system. The current case-control study was designed to determine the prevalence of toxoplasmosis in narcotic drugaddicted persons in comparison with healthy subjects using serology and molecular techniques in the southwest of Iran.

Methods: A total of 201 subjects (including 101 individuals with drug addiction and 100 control participants) were randomly selected. Chronic and acute toxoplasmosis was detected using the enzymelinked immunosorbent assay (ELISA) IgG avidity. T. gondii immunoglobulin G (IgG) and immunoglobulin M (IgM) were also determined by the ELISA. Moreover, the presence of T. gondii in blood samples was diagnosed using the nested-polymerase chain reaction (Nested-PCR).

Results: For T. gondii IgG, 17 (17.0%) of 100 and 39 (38.6%) of 101 cases were diagnosed in the control participants and drug-addicted people, respectively [P=0.001, OR=3.071, CI= (1.591-5.929)]. Moreover, 16 (15.8) and 5 (5.0%) cases were positive for the B1 gene in the drug-addicted patients and controls by the nested-PCR technique, respectively [P=0.019, OR=3.576, CI= (1.257-10.179)]. However, no significant differences were found between the opium (n=64) and crystal methamphetamine (n=37) groups in terms of T. gondii IgG and IgM antibodies and the presence of the parasite in the blood (P>0.05).

Conclusion: The present results demonstrated that the outbreak of the infection was more frequent in narcotic drug-addicted persons than the controls using serology and molecular techniques.

Background: Alzheimer's disease (AD) is a major neurodegenerative disorder with multiple manifestations, including oxidative stress, brain-derived neurotrophic factor (BDNF) depletion, and cholinergic dysfunction. Capparis spinosa (C. spinosa) is identified as a potential source of nutrition for alleviating various ailments. The current study assessed the ameliorating properties of C. spinosa hydroethanolic extract on memory dysfunction and the possible roles of oxidative stress and BDNF in the scopolamine (Scop)-treated rats.

Methods: Forty male Wistar rats were divided into the following four groups: Control, Scop (2 mg/kg, intraperitoneal injection (i.p.)), Scop + C. spinosa 150, and Scop + C. spinosa 300 groups. The rats were given C. spinosa extract (150 or 300 mg/kg, oral) for 3 weeks. During the third week, Passive Avoidance (PA) and Morris Water Maze (MWM) tests were done to assess memory and learning performance. Finally, oxidative stress markers and BDNF in the brain tissue were evaluated.

Results: Scop injection was associated with a significant increase in the time latency and travelled distance to reach the platform during the learning phase of MWM In the probe test, the Scoptreated rats showed a lower time and distance in the target area. Furthermore, Scop injection significantly decreased the latency to enter the dark while increasing the dark time and the frequency of entries to the dark zone of the PA task. C. spinosa extract effectively reversed the behavioural changes induced by Scop. Treatment with the extract also significantly increased the levels of superoxide dismutase, catalase, thiols, and BDNF, while decreasing malondialdehyde production in the brains of the Scop-injured rats.

Conclusion: C. spinosa hydroethanolic extract successfully ameliorated Scop-induced memory impairment by modifying BDNF and oxidative stress markers in the brain of amnesic rats.

Background: Motivated by the exciting biological potential for the use of hybrid molecules in medicine and therapy. It is anticipated that the coumarin-chalcone hybrids for skeletal muscle and antianxiety action will be investigated using a chemical hybridization technique.

Objective: Due to its numerous benefits, including high effectiveness, mode of action at receptors, minimal adverse effects, and improved pharmacokinetic features, naturally occurring and synthesized hybrid compounds are prospective sources for novel drug development techniques. In opinion of these applications, we here designed some coumarin-chalcone hybrids and explored them for skeletal muscle and antianxiety potential.

Methods: Using a chemical hybridization strategy, coumarin-chalcone hybrids have been synthesized and evaluated for skeletal muscle and antianxiety activity. The target compounds were synthesized by reaction of 7-hydroxy-4-methylcoumarion with haloalkane to afford 7-(2- bromoethoxy)-4-methyl-2H-chromen-2-one which was further treated with hydroxychalcones. The structures of target compounds were confirmed on the basis of their Melting Point, Thin Layer Chromatography, IR, 1HNMR and Mass studies. The computational properties of target compounds were also determined through online software. Skeletal muscle and antianxiety potential were performed in Swiss albino mice.

Results: The coumarin-chalcones hybrids showed skeletal muscle and antianxiety potential in Swiss albino mice and computational properties of the target compounds were also showed similarity as compared with diazepam.

Conclusion: Among the target compounds, the fluoro group containing compound was found to be more potent as compared to the standard drug diazepam.

Background: Depression and anxiety are the most common mental disorders worldwide.

Objective: We aimed to review silymarin and silibinin effects and underlying mechanisms in the central nervous system (CNS) for depression and anxiety treatment.

Methods: The research protocol was prepared based on following the PRISMA statement. An extensive search was done in essential databases such as PubMed, Cochrane Library, Web of Science (ISI), Embase, and Scopus. Considering the study inclusion and exclusion criteria, 17 studies were finally included. The desired information was extracted from the studies and recorded in Excel, and the consequences and mechanisms were reviewed.

Results: Silymarin and silibinin upregulated brain-derived neurotrophic factor (BDNF) and improved neural stem cells (NSCs) proliferation in the cortex and hippocampus. They also increased neurochemical serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels. Silymarin and silibinin reduced malondialdehyde (MDA) formation and increased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities. In addition, silymarin and silibinin reduced interleukin (IL)-6, IL-1β, and IL-12β, reducing tumor necrosis factor α (TNF-α) induced neuroinflammation.

Conclusion: Silymarin and silibinin exert anti-depression and anxiolytic effects by regulating neurotransmitters, endocrine, neurogenesis, and immunologic systems. Therefore, as natural and complementary medicines, they can be used to reduce the symptoms of depression and anxiety; However, more clinical studies are needed in this field.