Central nervous system agents in medicinal chemistry最新文献

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.

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.

Background: Putranjiva roxburghii Wall is traditionally known to cure many pathological conditions including epilepsy.

Objective: The present study is aimed at determining bioactive compounds in ethanolic extract of Putranjiva roxburghii test extract (PRTE) seeds by GCMS analysis and to assess its antiepileptic potential using various experimental models of epilepsy.

Methods: The ethanolic extract of seeds of Putranjiva roxburghii was subjected to GC-MS analysis to detect the bioactive phytoconstituents. Acute oral toxicity of the extract was performed using OCED guideline 420. Pentylenetetrazol (PTZ) kindling model of epilepsy and Maximal electroshock epilepsy (MES) model of epilepsy were used to determine anti-epileptic potential.

Results: The GC-MS analysis of the extract revealed the presence of 20 phytoconstituents. The major phytoconstituents included n-Propyl heptyl ether (25.25%), 5-Ethyl hydantoin (8%), octadec- 9-enoic acid (16.25%) and 1, 2-Benzene dicarboxylic acid (11.86%). The PRTE (50 mg/kg and 100 mg/kg) afforded a significant and dose-dependent protection against PTZ-induced kindling epilepsy and MES induced epilepsy (p<0.001 and p<0.01).

Conclusion: Based on the above findings, it is evident that Putranjiva roxburghii seeds contain biologically active compounds. It can also be concluded that the extract possesses anti-epileptic potential.

Objective: The study was designed to investigate the anti-nociceptive activity of Euphorbia hirta leaf and its possible mechanism of action.

Methods: The extract of Euphorbia hirta obtained from the leaf was prepared as per standard procedures and evaluated at the three doses (300, 600, and 1200 mg/kg, i.p). The extract was screened for anti-nociceptive activity using heat-induced (tail-flick) and chemical-induced (acetic acid-induced writhing and formalin-induced paw lick) nociception models in mice. The possible mechanism of action of the extract was evaluated using antagonists of notable nociceptive pathways.

Results: Intraperitoneal administration of Euphorbia hirta extract at the doses of 600 and 1200 mg/kg significantly (p<0.05) reduced the formalin-induced paw licking in both neurogenic and inflammatory phases of the test. While administration of the extract at the dose of 300 mg/kg significantly inhibited the pain due to formalin in the inflammatory phase but not in the neurogenic phase. The anti-nociceptive effect of Euphorbia hirta extract increased the reaction time to thermal stimulus, also inhibited the acetic acid-induced writhing dose-dependently. The antinociceptive effect exhibited by Euphorbia hirta extract in the formalin test was reversed by the administration of naloxone, theophylline, and atropine. Glibenclamide, nifedipine, and yohimbine, however, did not significantly block the anti-nociceptive effect of the extract. Meanwhile, methylene blue administration enhanced the anti-nociceptive effect of the extract.

Conclusion: The results indicated that Euphorbia hirta extract produces a dose-related antinociceptive effect in several models of chemical and thermal pain, through mechanisms that might involve interaction with adenosine, cholinergic, and opioid receptors.

The most common reason behind dementia is Alzheimer's disease (AD) and it is predicted to be the third life-threatening disease apart from stroke and cancer for the geriatric population. Till now, only four drugs are available on the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidence of molecular targets are the major hurdles for developing a new drug to treat AD. The rate of attrition of many advanced drugs at clinical stages makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repurposing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) consists of 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past, the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we have reviewed the clinical candidates for AD with emphasis on their development history, including molecular targets and the relevance of the target for AD.

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.

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.

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.

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.

Objective: In the current study, the synthesis, characterization, and neuropharmacology of quinazolinone tethered with aromatic (3a-3i) and heteroaromatic substitution (3j, 3k, and 3l) as effective anxiolytic agents are reported.

Background: Anxiety and depression are often comorbid with neurological as well as other medical maladies. Clinically known anxiolytics (Benzodiazepines) are accompanied by untoward sedation and other CNS depressive actions. The quinazolinone moiety is a privileged pharmacophore with a wide pharmacological spectrum. Herein, the synthesis, characterization, and neuropharmacological evaluation of some 2-substituted quinazolinone derivatives are reported.

Methods: The synthesized compounds were characterized using 1H-NMR and TLC analysis. Behavioral analysis was performed using EPM (Elevated Plus Maze), OFT (Open Field Test), PIST (Pentobarbital Induced Sleep Test), FST (Forced Swim Test) and PCPA (p-chlorophenyl alanine) bioassay. To further justify the therapeutic claim, systemic and neurotoxicological analysis of the most potent members of the series was performed using OECD mandated protocols. The studies showed that the compounds had a wide therapeutic window with >1000 mg/kg and >500 mg/kg LD50 and NOAEL, respectively.

Results: The compounds with an electronegative group in the quinazolinone nucleus (3f, 3e, 3d, and 3c) induced anxiolysis devoid of sedative adverse reaction. Besides, anti-depressant efficacy of 3f, 3e, 3d, and 3c observed in rodents was a result of a decrease in anxiety level. It was found that the neurotoxicology of the potent members (3f, 3e, 3d, and 3c) advocated their wide therapeutic window with >1000 mg/kg LD50 and >5000 mg/kg NOAEL.

Conclusion: Our findings of behavioral bioassays revealed that inducing an electronegative group into the quinazolinone nucleus yielded the most potent members of the series (3f, 3e, 3d, and 3c). The said compounds were found to produce anxiolysis and anti-depressive action without sedative-hypnotic side effects in rodent models. In summary, it can be stated that extending the studies in a clinical setting would furbish the contours of current anxiolytic therapy, especially in anxiety comorbid with medical maladies.