Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 23, Issue 3, 2023

Epilepsy is the most general, extensive, and severe neurological disorder, affecting more than 50 million individuals globally. Initially, conventional medicines and simple salts like potassium bromide were employed as antiepileptic medication candidates. Nowadays, large number of anticonvulsant drugs have been discovered as first-generati, second-generation and newer drugs which are still in development phases. The pharmacophore-based drug design process includes pharmacophore modeling and validation, pharmacophore-based virtual screening, virtual hits profiling, and lead identification with special to epilepsy. This comprehensive article reviews recently developed anticonvulsant derivatives on the basis of pharmacophoric approaches. A literature survey was performed using various search engines like Google Scholar, Scopus, Sci Finder, ScienceDirect, Science gate, Scilit, PubMed, NINDS database of NIH, Bentham Sciences, and other online and print journals and scientific databases for compilation of this review article. The presented review discusses newer drugs that are in the market as well as in various clinical trial phases. Detailed outcomes of pharmacophoric modeling have been discussed for newly derived derivatives like targets involved in Epilepsy, lead molecules etc., for the treatment of epilepsy. This exhaustive review will assist the researchers in the further development of potential antiepileptic agents.

Background: Simultaneously with studies on animal models of fetal-induced maternal immune activation, related studies documented behavior, neurophysiological, and/or neurochemical disorders observed in some neuropsychiatric disorders, including autism and schizophrenia. Objective: To investigate whether treatment tianeptine might ameliorate maternal immune activation (MIA)-induced behavioral deficits in the offspring. Materials and Methods: The pregnant mice were injected through tail vein injection at a concentration of 5 mg/kg of polyriboinosinic-polyribocytidilic acid (polyI:C) and/or used saline as a vehicle. The injection was performed on the 9th day of pregnancy. Each group of MIA offspring was subjected to vehicle, clozapine, or tianeptine treatment. Results: In prepulse inhibition (PPI) test, oral treatment with tianeptine ameliorated MIA-induced sensorimotor gating deficit. Most behavioral parameters of social interaction test (SIT), forced swimming test (FST), and open field test (OFT) were significantly changed in the MIA offspring. Tianeptine treatment significantly recovered behavioral changes observed in the SIT, OFT, and FST. In order to confirm expression level of neurodevelopmental proteins, immunohistochemical image analysis and Western blot were performed, and the medial prefrontal cortex (mPFC) was targeted. As a result, it was confirmed that the neurodevelopmental proteins were decreased, which was recovered after administration of tianeptine to MIA offspring. Conclusion: Tianeptine might be useful for treating psychiatric disorders with neurodevelopmental issues.

Background: The most prominent adipokine, adiponectin (APN), has an adverse relationship with the malfunction of adipose tissue. Obesity causes a decrease in plasma APN levels, which eventually results in insulin resistance and diabetes. In this study, we assessed how the effects of APN on memory are influenced by the insulin receptor substrate-1 (IRS-1) and the mammalian target of rapamycin (mTOR) pathways. Methods: Streptozotocin (STZ) 3 mg/kg intracerebroventricular injections on days 1 and 3 following cannulation were used to create an animal model of Alzheimer's disease. The acquisition phase was preceded by injections of MHY and adiponectin. For the passive avoidance task, the stepthrough latency and total duration in the dark compartment were recorded and evaluated, and the preference index was calculated for the novel object identification test. IRS-1 protein expression in the hippocampus was assessed by western blotting. Results: STZ reduced the step-through latency (STL), which rose significantly (P≤0.001) in the APN+STZ group. The memory-improving effects of APN were reversed when MHY was administered first (P≤0.001). The STZ and APN+STZ+MHY groups both had a substantial decline in the preference index (P≤0.01). Compared to the control group, the STZ group's expression of the IRS- 1 protein was dramatically reduced (P≤0.0001). In contrast to the APN+STZ group, the MHYtreated group likewise showed decreased IRS-1 protein expression (P≤0.0001), but APN+STZ was able to enhance IRS-1 expression rate (P≤0.0001). Conclusion: In a rat model of AD, we found that adiponectin improved aversive and cognitive memory, which is at least partially mediated by the mTOR signaling cascade.

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: Oxidative stress is an important contributor to Alzheimer's disease. Olibanum has therapeutic effects on various diseases. The effect of Olibanum on memory deficit induced by scopolamine (Sco) was challenged. Methods: Four groups were considered as (1) control (2) Sco, (3-4) Sco - Olib 100 and 200 mg/kg. Treatment by Olib or vehicle was done for two weeks. The third week was accompanied by the Morris water maze (MWM) and passive avoidance (PA) with Sco injection. On the last day, the brain and hippocampus were used for evaluation of the malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and a total thiol group. Results: Sco increased the traveled time and distance to reach the hidden platform during five days of learning (P<0.01 - P<0.001) whereas it decreased the traveled time and distance (P<0.05- P<0.01) in the target area during the probe test of MWM. Sco also decreased delay time in the PA test (P<0.05 - P<0.001). Sco also decreased CAT, SOD, and thiol, whereas it, increased MDA in both the cortex and hippocampus (P<0.01 - P<0.001). Olib attenuated the impaired performance of the rats induced by Sco in MWM and PA tests. Olib reversed the increasing effects of Sco on MDA in both cortex and hippocampus and also reversed the attenuating effects of Sco on CAT, SOD, and thiol. Conclusion: Olib had an inhibitory effect on memory deficit induced by Sco probably through its anti-oxidant property.

Introduction: Mental disorders during pregnancy are one of the major public health problems because of its effect on both mother and child, but the prevalence of psychiatric disorders in infertile women is largely unknown to compare psychiatric disorders during and after pregnancies with assisted reproductive therapies (ART) and spontaneous pregnancies. Methods: This cross-sectional study was conducted on pregnant women referring to midwifery centers in Ahvaz City in 2022. Pregnant women were included in two groups of either pregnancy caused by ART (n= 84) or spontaneous pregnancy (n= 256). The Symptom Checklist-90-R (SCL- 90-R) was used to assess psychiatric disorders during and after pregnancies. Results: A high percentage of women with spontaneous pregnancy (74.6%) and ART (91.7%) had some degree of psychological disorders. The severity of psychological disorders in both groups was higher during pregnancy than after pregnancy (p<0.001). The intensity of various psychological disorders during and after pregnancy in the ART pregnancy group was significantly higher than the control group (p<0.001). An increased risk of psychiatric disorders during pregnancy was associated with the history of psychiatric disorders [odd ratio (OR): 12.393; P= 0.022], family history of psychiatric disorders (OR:26.168; p<0.001), history of infertility (OR: 19.00; p<0.001), primary infertility (OR: 12.714; P=0.004), infertility duration more than three years (OR: 43.424; p<0.001), and frequency of embryo transfer (OR: 18.939; P=0.045). Conclusion: Psychiatric disorders were prevalent among pregnant women in the study area especially in pregnant women with ART. Regular screening programs for mental health problem should be included in an antenatal care service especially in this high-risk group.

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.