Human Gamma-aminobutyric Acid Receptor Research Articles

Evaluation of anxiolytic, sedative, and antioxidant activities of Vitex peduncularis Wall. leaves and investigation of possible lead compounds through molecular docking study

Vitex peduncularis, belongs to the Verbenaceae family, locally known as ‘Boruna’, ‘Horina’, ‘Ashmul gaas’, is commonly used for treating various chronic diseases in the folk medicine such as malarial fevers, jaundice, diabetes, chest pain, joint ache, abnormality in eyes & face, and urethritis, etc. In the present study, we investigated the anxiolytic, sedative, and antioxidant activities of ethanol extract of V. peduncularis leaves (EEVP) in both in vivo and in vitro models. Then, a molecular docking analysis was carried out to determine the possible lead compounds of EEVP for the biological properties described above. The anxiolytic and sedative activity of EEVP was determined using hole board and hole cross tests, respectively. Antioxidant activity was measured using DPPH and FRPA assays, whereas docking was done by using the Schrodinger suite (Maestro v10.1). Our result demonstrated that EEVP has significant and dose-dependent anxiolytic and sedative activity at the doses of 200 and 400 mg/kg (b.w.) in both models. This study also exhibited that EEVP has significant antioxidant activity compared to reference standard ascorbic acid. The molecular docking study revealed that 3,4-dihydroxybenzoic acid, 4-hydroxybenzoic acid, and vitexilactone have the best binding affinities against the target receptors (potassium channel receptor, human gamma-aminobutyric acid receptor, and human peroxiredoxin 5) for anxiolytic, sedative, and antioxidant activities. The present study confirmed that EEVP has anxiolytic, sedative, and antioxidant properties, which could be because of the occurrence of various phytochemicals and three bioactive phytocompounds which found potential during molecular docking analysis.

Microwave Assisted Synthesis and Molecular Docking Studies of Some 4- (3H)-quinazolinone Derivatives as Inhibitors of Human Gamma- Aminobutyric Acid Receptor, the GABA (A)R-BETA3 Homopentamer.

Quinazolines and quinazolinones constitute a major class of biologically active molecules, both from natural and synthetic sources. The quinazolinone moiety is an important pharmacophore showing many types of pharmacological activities as shown in recent exhaustive review on the chemistry of 2-heteroaryl & heteroalkyl-4-quinazolinones4-quinazolinones that are the formal condensation products of anthranilic acid and amides. They can also be prepared in this fashion through the Niementowski quinazolinone synthesis, named after it's discoverer Stefan Niementowski. Quinazoline and condensed quinazoline exhibit potent central nervous system (CNS) activities like anti-anxiety, analgesic, anti-inflammatory and anticonvulsant. Quinazolin-4- ones with 2, 3-disubstitution is reported to possess significant analgesic, anti-inflammatory and anticonvulsant activities. To expand these views and application profiles, efforts have been made for the synthesis of a new class of quinazolinone by incorporating different amines into synthesized benzoxazinone ring by replacing O atom in the ring. Up till now, a great number of various procedures have been proposed for the synthesis of quinazolin-4-ones in the past few years. Using microwave radiation, this reaction could be easily and rapidly performed in very good yields, providing a large number of various 3-substituted-2- propyl-quinazolin-4-one derivatives which can be employed as useful bioactive compounds. We report a facile and efficient method for the synthesis of 3-substituted-2- propyl-quinazolin-4-one by the condensation reaction of anthranilic acid or halogen substituted anthranilic acid or methyl anthranilate, butanoic anhydride with various amines. We also report a drug/ligand or receptor/protein interactions by identifying the suitable active sites in the human gamma-aminobutyric acid receptor, the gaba (a)r-beta3 homopentamer human gammaaminobutyric acid receptor, and the gaba (a)r-beta3 homopentamer protein. It was observed in the reaction, 3-alkyl/aryl-2-alkyl-quinazolin-4-one gave good yield as well as good quality of the product by using MW. All the synthesized compounds were subjected to grid-based molecular docking studies. The results show that compound 4t has good affinity to the active site residue of the human gamma-aminobutyric acid receptor, and the gaba (a)r-beta3 homopentamer. The Microwave irradiation for the synthesis of the title compounds offers a reduction in reaction time, operation simplicity, cleaner reaction, easy work-up and improved yields. The procedure clearly highlights the advantages of green chemistry. The data reported in this article may be helpful for the medicinal chemists who are working in this area. The protein-ligand interaction plays a significant role in structural based drug designing. In the present work, we have docked the ligand, 2, 3-disubstituted quinazolinone with the proteins that are used as the target for GABA-A receptor.

Molecular docking and biological evaluation of some thioxoquinazolin-4(3H)-one derivatives as anticancer, antioxidant and anticonvulsant agents

BackgroundThe quinazoline are an important class of medicinal compounds that possess a number of biological activities like anticancer, anticonvulsant and antioxidant etc.ResultsWe evaluated the previously synthesized quinazoline derivatives 1–3 for their anticancer activities against three cancer cell lines (HepG2, MCF-7, and HCT-116). Among the tested compounds, quinazolines 1 and 3 were found to be more potent than the standard drug Vinblastine against HepG2 and MCF-7 cell lines. All the tested compounds had less antioxidant activity and did not exhibit any anticonvulsant activity. Also, molecular docking studies were performed to get an insight into the binding modes of the compounds with human cyclin-dependent kinase 2, butyrylcholinesterase enzyme, human gamma-aminobutyric acid receptor. These compounds showed better docking properties with the CDK2 as compared to the other two enzymes.ConclusionsThe overall study showed that thioxoquinazolines are suitable antitumor agents and they should be explored for other biological activities. Modification in the available lot of quinazoline and synthesis of its novel derivatives is essential to explore the potential of this class of compounds. The increase in the threat and with the emergence of drug resistance, it is important to explore and develop more efficacious drugs.

Synthesis and Structure−Activity Relationships of 1-Phenyl-1H-1,2,3-triazoles as Selective Insect GABA Receptor Antagonists

To study the interaction of phenylheterocycles with gamma-aminobutyric acid (GABA) receptors, 4- or 5-alkyl(or phenyl)-1-phenyl-1H-1,2,3-triazoles were synthesized and examined for their ability to inhibit the specific binding of [3H]-4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a noncompetitive antagonist, to the housefly and rat GABA receptors, as well as to the beta3 subunit homo-oligomer of the human GABA receptor investigated as a model receptor. 4-Substituted 1-phenyl-1H-1,2,3-triazoles were found to be more potent competitive inhibitors than the 5-substituted regioisomers in the case of all receptors. The 4-tert-butyl or 4-n-propyl analogue of 1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazole exhibited the highest level of inhibition of [3H]EBOB binding to all receptors. Most of the synthesized analogues were more active in terms of the inhibition of EBOB binding to the housefly and human beta3 GABA receptors than to the rat receptor. The 4-cyclohexyl analogue showed the highest (185-fold) housefly versus rat receptor selectivity. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis demonstrated that both the 4-trifluoromethyl-2,6-dichloro substitution on the phenyl ring and a small, bulky, hydrophobic substituent at the 4-position of the triazole ring played significant roles in conferring high potency in cases involving the housefly and human beta3 receptors. The human beta3 receptor resembled the housefly receptor in terms of their recognition of phenyltriazoles, whereas 3D-QSAR analysis revealed a slight difference between the two receptors in terms of their mechanisms of recognition of the para-substituent on the phenyl moiety. Some of the triazoles synthesized here exhibited insecticidal activity, which was correlated with their ability to inhibit [3H]EBOB binding to the housefly receptor. Thus, 1-phenyl-1H-1,2,3-triazoles with the appropriate substituents exert insecticidal activity by selectively acting at the site for noncompetitive antagonism of insect GABA receptors.

Identification of SNPs in human gamma aminobutyric acid A receptor γ2 gene

Gamma aminobutyric acid (GABA) is a major inhibitory neurotransmitter. Because of its importance and diverse functions, studies of single nucleotide polymorphisms in the GABA receptor genes are of great significance, which may produce useful molecular markers for genetic analysis of neurological disease, and possibly lead to the discovery of pathogenic mutations. We identified eleven SNPs in the entire exon regions, immediate intron regions and promoter region of human GABA receptor gamma2 gene by direct sequencing. In this discovery, 2 non-synonymous cSNPs and 1 splicing variant are found.

Quinolones, theophylline, and diclofenac interactions with the gamma-aminobutyric acid receptor.

Epileptic seizures and hallucinations, which are rare in patients receiving quinolones, have been observed more frequently in patients receiving both quinolones and either theophylline or nonsteroidal anti-inflammatory drugs. Inhibition of gamma-aminobutyric acid (GABA) binding to the GABA receptor, resulting in general excitation of the central nervous system, may be the underlying mechanism of these adverse phenomena. We demonstrate here that ciprofloxacin displaced a GABA-like substance (muscimol) from the GABA receptor when administered in concentrations of greater than 10(-4) M. These concentrations were lower than those needed by pefloxacin, ofloxacin, and nalidixic acid to reach a concentration that inhibits 50% of binding. The combination of ciprofloxacin and theophylline was additive in reducing the level of muscimol binding to the GABA receptor, whereas a diclofenac-ciprofloxacin combination had no effect. The concentrations of both ciprofloxacin and the other quinolones used were much higher than those observed in human serum and cerebrospinal fluid in a clinical setting; however, different human GABA receptor affinities, preexisting GABA excitation, or underlying central nervous system disease may amplify the excitatory side effects observed by the co-administration of quinolones and theophylline. Attention should be paid to the possible epileptogenic activity of the simultaneous administration of quinolones with aminophylline, nonsteroidal anti-inflammatory drugs, or other unpredictable drugs.