Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 20, Issue 2, 2020

The two main problems in the pharmacotherapy of epilepsy are resistance to currently available first-line medications (which occurs in about one third of patients) and the high incidence of side effects. To address these two challenges, extensive efforts are being undertaken to design new, structurally distinct antiepileptic drugs with a broad spectrum of anticonvulsant activity. Tests in animal models of epilepsy indicate that α-substituted lactams and acetamides show a broad spectrum of anticonvulsant activity (including very promising activity in drug-resistant models) as well as an excellent safety profile. Limited clinical results confirm these preclinical findings. In the first part of this review, pharmacology and toxicology of α-substituted lactams and acetamides and their putative protein targets in the brain have been discussed. This is followed by a discussion of structure-activity relationships among α-alkyl-, α-aryl-, and α-aryl-α-alkyl-substituted derivatives. The most promising structures seem to be those related to 3-ethyl-3-phenylpyrrolidin-2-one, 2-phenylbutyramide, and 2- sec-butylvaleramide. The information presented in this review is expected to facilitate rational drug design and development efforts for α-substituted lactams and acetamides.

A vast advancement has been made in the treatment related to central nervous system disorders especially Parkinson’s disease. The development in therapeutics and a better understanding of the targets results in upsurge of many promising therapies for Parkinson’s disease. Parkinson’s disease is defined by neuronal degeneration and neuroinflammation and it is reported that the presence of the neurofibrillary aggregates such as Lewy bodies is considered as the marker. Along with this, it is also characterized by the presence of motor and non-motor symptoms, as seen in Parkinsonian patients. A lot of treatment options mainly focus on prophylactic measures or the symptomatic treatment of Parkinson’s disease. Neuroinflammation and neurodegeneration are the point of interest which can be exploited as a new target to emphasis on Parkinson’s disease. A thorough study of these targets helps in modifications of those molecules which are particularly involved in causing the neuronal degeneration and neuroinflammation in Parkinson’s disease. A lot of drug regimens are available for the treatment of Parkinson’s disease, although levodopa remains the choice of drug for controlling the symptoms, yet is accompanied with significant snags. It is always suggested to use other drug therapies concomitantly with levodopa. A number of significant causes and therapeutic targets for Parkinson’s disease have been identified in the last decade, here an attempt was made to highlight the most significant of them. It was also found that the treatment regimen and involvement of therapies are totally dependent on individuals and can be tailored to the needs of each individual patient.

Background: A correlation between cognitive dysfunctions and brain insulin resistance has been established by several clinical and experimental studies. Consistent data support that people diagnosed with brain insulin resistance, resulted from diabetes, have shown an increased risk of presenting cognitive dysfunctions, clinical signs of dementia and depression, then speculating a role of dysregulations related to insulin signalling in these diseases. Furthermore, it is currently discussed that Ca2+ signalling, and its dysregulations, may be a factor which could correlate with brain insulin resistance and cognitive dysfunctions. Objective: Following this, revealing this interplay between these diseases may provide novel insights into the pathogenesis of such diseases. Methods: Publications covering topics such as Ca2+ signalling, diabetes, depression and dementia (alone or combined) were collected by searching PubMed and EMBASE. Results: The controlling of both neurotransmitters/hormones release and neuronal death could be achieved through modulating Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling). Conclusion: Taking into account our previous reports on Ca2+/cAMP signalling, and considering a limited discussion in the literature on the role of Ca2+/cAMP signalling in the link between cognitive dysfunctions and brain insulin resistance, this article has comprehensively discussed the role of these signalling pathways in this link (between cognitive dysfunctions and brain insulin resistance).

Background: Drug repositioning is becoming popular due to the development of resistance to almost all the recommended antimalarials. Pregabalin and gabapentin are chemical analogs of gamma- aminobutyric acid (GABA) approved for the treatment of epilepsy and neuropathic pain. Objective: This study investigates acute toxicities and antimalarial activities of pregabalin and gabapentin in the murine malarial model. Methods: Acute toxicities were assessed using the method of Lorke, while curative activities were assessed by the administration of serial doses of pregabalin and gabapentin to Plasmodium berghei infected mice. Pregabalin was further investigated for its prophylactic activity, and curative potential when combined with either artesunate or amodiaquine. All drugs were freshly prepared and administered orally. Thin films were collected, stained, and observed under the microscope for the estimation of parasitemia and calculation of percentage chemoinhibition or chemoprevention. In pregabalin –artesunate or -amodiaquine combination aspect of this study, survival day post-infection (SDPI) was recorded, while parasitemia was re-estimated for animals that survived till day 28. Results: The oral LD50 of gabapentin, as well as pregabalin, was >5,000 mg/kg. Gabapentin at 100 and 200 mg/Kg demonstrated 35.64% and -12.78% chemoinhibition, respectively, while pregabalin demonstrated 75.60% and 100.00% chemoinhibition at doses of 12.5 and 25 mg/Kg, respectively. Moreover, pregabalin at individual doses of 25, 50 mg/Kg, and in combination with either artesunate or amodiaquine demonstrated 100.00% chemoinhibition. In its prophylactic study, pregabalin was found to be 100% chemopreventive at individual doses of 12.5 and 25 mg/Kg. Conclusion: Both GABA analogs have antimalarial properties, but pregabalin proved to be more efficacious.

Background: Suaeda vermiculata is one of the widely distributed halophytes in central Saudi Arabia. The plant is used as a remedy for liver diseases, jaundice, and inflammation. S. vermiculata is also used as camels' food by local shepherds. Purpose: The study aims to evaluate the behavioral antidepressant and anxiolytic effects of S. vermiculata aqueous and ethanol extracts. Methods: Aqueous and ethanol extracts of S. vermiculata were prepared by the maceration technique. Standard forced swim test cylinder and light/dark chamber device were used to evaluate the antidepressant and anxiolytic activities of the extracts (200 mg/kg) in rats model, respectively. Results: The aqueous and ethanol extracts of S. vermiculata showed remarkable antidepressant activity with significant increase in the swimming time and reduced immobility in the rats compared to imipramine treated animals (P<0.05). Ethanol extract increased the swimming time by 20% and decreased the immobility time by more than 60% compared to the control group of animals. In contrast, the extracts induced the anxiety behavior in experimental rats compared to vehicle- treated animals. The extracts significantly (P<0.001) reduced the time spent by rats in the light chamber by more than 50% and increased the time spent in dark chamber as compared with the control group and the group receiving diazepam. Conclusion: The medicinally important plant S. vermiculata induced anxiety behavior with antidepressant activity in rats. These effects from our point of view are similar to the effects of some common beverages containing caffeine such as coffee and tea.

Background: Drugs used for Parkinson's disease (PD) are mainly responsible for only relieving major symptoms, but may present several side effects that are typical of such pharmacological treatment. Methods: This study aimed to use in silico methods for drug designing inhibitors of the PD therapeutic target, monoamine oxidase B (MAO-B). Thus, 20 MAO-B inhibitors from the BindingDB database were selected followed by a calculation of their descriptors at DFT B3LYP/6-31G** level of theory. Results: Statistical analysis considering a Pearson correlation matrix led to the selection of electrophilicity index as a descriptor related to the biological activity of inhibitors. Furthermore, based on the prediction of suitable ADME/Tox properties, the molecule CID 54583085 was selected as a template to carry out structural modifications to obtain 3 analogues, whereas molecules B and C showed significant improvement in mutagenicity and carcinogenicity, in relation to the template. Conclusion: Thus, it is concluded that the proposed modifications led us to satisfactory results, since there was an improvement in the toxicological properties of molecules, however, further studies must be carried out to evaluate their biological activities as possible MAO-B inhibitors for PD treatment.

Objective: To determine the potential effect of Pyrenancantha staudtii extract on experimentally induced seizures in mice and to evaluate the role of benzodiazepines, naloxone, and serotonin within these pathways. Methods: Animal behaviours were evaluated using open field, hexobarbitone-induced sleep model, and anticonvulsant activity using picrotoxin-, or strychnine-, or isoniazid-induced convulsions. Attempt to understand the mode of action of the anticonvulsant activity of the plant, three notable antagonists (flumazenil, 3 mg/kg; naloxone 5 mg/kg, i.p., and cyproheptadine, 4 mg/kg, i.p) were used. Results: The results revealed a significant (p < 0.05) reduction in the frequency of rearing and grooming episodes compared with the control. The extract of P. staudtii potentiates the sleeping time of hexobarbitone-induced hypnosis in a dose-related manner. P. staudtii stem bark extracts significantly (p<0.05) prolonged the onset of a seizure and attenuated the duration of seizure in a dose-dependent manner in picrotoxin- and or isoniazid-induced seizures. While, P. staudtii stem bark extract at all doses (100, 200, and 400 mg kg-1) though significantly prolonged the onset of action, but did not confer any significant changes on the duration, as well as mortality in this strychnine-induced seizure model. However, the anticonvulsant activity of the methanolic extract of P. staudtii was significantly reversed following intraperitoneal pre-treatment with flumazenil (GABA receptor antagonist) and naloxone (opioid receptor antagonist) but not cyproheptadine (5-HT2 receptor antagonist) in picrotoxin-induced convulsion. Conclusion: The data obtained suggest that methanol extract of P. staudtii possessed significant anticonvulsant effect, thereby confirming the traditional uses of P. staudtii in the treatment of epilepsy; mechanisms of which could involve the interaction with GABAergic and or opioidergic system.