Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 21, Issue 3, 2021

Background: A series of phenylurea derivatives were designed and synthesized, The target compounds were subjected to pharmacological studies. Various other parameters such as physicochemical properties, computational studies, and % similarity were also calculated. Materials and Methods: The synthesis of the target compounds has been carried out by reaction of Phenylurea with chloroacetyl chloride to afford 1-(2-chloroacetyl)-3-phenylurea, which further reacted with substituted anilines. All the reactions were monitored by TLC. All the target compounds were purified by recrystallization and characterized by spectroscopic methods. Physicochemical parameters and Log P values of the synthesized derivatives were also calculated. It identified compounds that have the prospect to cross the blood-brain barrier (BBB) and are CNS active. Skeletal muscle relaxant activity was also carried out using the Rotarod method. Results: The data of Log P indicated that the synthesized compounds have the potential to cross the BBB, so they are CNS active. Pharmacological activities of the derivatives showed that the compounds containing chloro group have moderate skeletal muscle relaxant activity. The test compounds possess significant differences between the control group and the treated group. Conclusion: The synthesized derivatives containing chloro group were found to be more potent when compared to standard drug Diazepam. Various others parameters studied revealed that the drug has the potency to cross the blood-brain barrier.

Background: Apart from being an essential heavy metal, Manganese (Mn) serves as an important component of the antioxidant enzyme system in humans. Overexposure to manganese leads to the development of manganism, which is characterized by motor dysfunction along with neurodegeneration. The management of manganism often utilizes chelation therapy. In this regard, Monoisoamyl-2, 3-Dimercaptosuccinic Acid (MiADMSA) has been reported as a novel arsenic chelator, due to the presence of vicinal sulfhydril group. MiADMSA has been reported to reduce the level in divalent ions (like copper) therefore, it may be hypothesized that MiADMSA would be helpful in Mn-induced neurotoxicity. Objective: This study is envisaged to explore the protective effect of MiADMSA on Mn-induced neurotoxicity. Methods: Mn exposure was carried out by intraperitoneal administration of Mn (as manganese chloride, 10 mg/kg; i.p.). The animals were treated with MiADMSA (50 mg/kg; p.o.) either alone or in combination with Mn. The effect of different treatments on neurobehavioral functions was observed by assessing spontaneous locomotor activity, motor rotarod test, and depression-like behavior in the forced swim test. After behavioral evaluations, all the animals were sacrificed and the brain and liver were isolated for metal estimations. Results: Mn exposure leads to loss of motor coordination as observed in spontaneous locomotor activity and rotarod test. However, treatment with MiADMSA significantly improved motor impairments as compared to Mn exposed animals. Accumulation of Mn in the liver and brain has been recorded with Mn exposure; however, MiADMSA treatment significantly reduced the Mn content from the liver and brain. Conclusion: The outcome of the study suggests that treatment with MiADMSA reversed Mn-induced neurotoxicity by reducing Mn load. Therefore, the use of MiADMSA may be suggested in manganese toxicity, after careful investigation.

Background: Existing neuroprotective drugs are not effective enough to treat alcoholic encephalopathy. This makes the development of novel pharmacological approaches to treating patients with ethanol-induced neurodegeneration(EIN) relevant. Therefore, the search for new targets among intracellular signaling molecules of regeneration-competent cells of nervous tissue is promising. Objective: This study aims to explore the involvement of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) in the realization of the functions of nervous tissue progenitors and glial cells in EIN. Methods: Experiments were conducted on mice of C57B1/6. EIN was modeled in vitro and in vivo. The effects of the adenylate cyclase (AC) and PKA inhibitors on the colony-forming capacity of neural stem cells (NSC) and neuronal-committed progenitors (NCP), their proliferative activity, and intensity of specialization were investigated. The secretion of neurotrophins by astrocytes, oligodendrocytes, and microglial cells was also evaluated. Individual fractions of cells were obtained using the immunomagnetic separation method. Results: The cAMP/PKA signaling is shown to stimulate the proliferation of the NSC and inhibit the mitotic activity of the NCP under the conditions of their optimal vital activity. cAMP reduces the specialization intensity of both types of progenitors. EIN leads to the inversion of the role of the cAMP/PKA-pathway in the regulation of NSC functions. cAMP-pathway has varying influences on the secretion of neurotrophic growth factors by glial cells depending on their living conditions. AC blockage stimulates the realization of the NSC and NCP growth potential and production of neurotrophins by astrocytes and microglial cells in EIN. Conclusion: These findings show the potential for the use of AC inhibitors as novel effective drugs for the therapy of alcoholic encephalopathy.

Background: Morphine independently reduces the expression level of Brain-derived Neurotrophic Factor (BDNF) and Cyclic-AMP Response Element Binding protein (CREB). BDNF and CREB play a vital role in protecting and regulating the proper functioning of neurons. There has not been any study on the effect of methadone maintenance treatment and its comparison with morphine. Therefore, this study was conducted to examine the effect of methadone maintenance on the expression of BDNF and CREB genes in brain VTA of male morphine treated rats. Methods: In this study, 24 Wistar rats (200-250g) were assigned to three experimental groups: 1) Animals without morphine treatment (control); 2) Morphine treated animals (10 mg/kg, twice/day through subcutaneous injection for 21 days); 3) Animals under methadone maintenance after treatment with morphine (maintenance dose of methadone was achieved during 14 days equal to 1 mg per 100 ml at the first week and 2.5 mg per 100 ml at second week). To evaluate the expression of BDNF and CREB genes, real time PCR method was used, and ELISA was applied to measure the serum level of BDNF protein at the end of the experiment. Results: According to the findings of this study, similar to morphine treated group, methadone maintenance in morphine treated animals led to a significant reduction in the expression of BDNF and CREB genes at VTA as well BDNF serum level compared with the control group. Conclusion: It was concluded that methadone, like morphine, causes a significant reduction in the expression of BDNF and CREB genes in the brain VTA area of rats as well as BDNF serum level compared with the control group.

Background: Puberty is a developmental transition in which an estrogenic surge occurs, mediating the release of xenoestrogens, like aluminium. Aluminium’s effect on anxiety in rodents at the different developmental stages is inconsistent. Aims: This study aimed at investigating the effect of the metalloestrogenic property of aluminium on anxiety-like behavioral changes in prepubertal and young adult female rats. Objective: Considering this aim, our objective was to evaluate the anxiety-like behavior by the elevated plus maze in prepubertal and young adult female rats with or without acute exposure to aluminium. Methods: To address this property of aluminium, 5mg/Kg body weight (Al-5) and 10 mg/Kg body weight (Al-10) of aluminium was administered intraperitoneally to female rats at two developmental stages, prepubertal (PP; n = 8 for each dose) and young adult (YA; n = 6 for each dose) for two weeks. Post-treatment, three days behavioral assessment of the rats was done employing elevated plus maze. Results: Reduced escape latency was seen in Al-5, Al-10 pre-pubertal rats, and Al-5 young-adult rats on day 3. A significant reduction in open arm time was seen in the Al-5 young-adult rats. Aluminium treatment in the pre-pubertal rats reduced their head dipping and grooming. Reduced sniffing, head dipping, and stretch-attended posture in the treated young-adult female rats showed that they had impaired risk-taking tendency. Conclusion: Differential effect on the anxiety-like behavior in the pre-pubertal and young-adult female rats might be due to the metalloestrogenic property of aluminium, acting differently on the two age groups.

Aim: The aim of the present study was to apply pharmacophore based virtual screening to a natural product database to identify potential PDE1B inhibitor lead compounds for neurodegenerative and neuropsychiatric disorders. Background: Neurodegenerative and neuropsychiatric disorders are a major health burden globally. The existing therapies do not provide optimal relief and are associated with substantial adverse effects. This has resulted in a huge unmet medical need for newer and more effective therapies for these disorders. Phosphodiesterase (PDEs) enzymes have been identified as potential targets of drugs for neurodegenerative and neuropsychiatric disorders, and one of the subtypes, i.e., PDE1B, accounts for more than 90 % of total brain PDE activity associated with learning and memory process, making it an interesting drug target for the treatment of neurodegenerative disorders. Objectives: The present study has been conducted to identify potential PDE1B inhibitor lead compounds from the natural product database. Methods: Ligand-based pharmacophore models were generated and validated; they were then employed for virtual screening of Universal Natural Products Database (UNPD) followed by docking with PDE1B to identify the best hit compound. Results: Virtual screening led to the identification of 85 compounds which were then docked into the active site of PDE1B. Out of the 85 compounds, six showed a higher affinity for PDE1B than the standard PDE1B inhibitors. The top scoring compound was identified as Cedreprenone. Conclusion: Virtual screening of UNPD using Ligand based pharmacophore led to the identification of Cedreprenone, a potential new natural PDE1B inhibitor lead compound.