Novel 3-Substituted-2, 3-Dihydro-2-Thioxoquinazolin-4-(1H)-one derivative as Anticonvulsants: Synthesis, Molecular Docking and Pharmacological Screening

2020 ◽  
Vol 17 (6) ◽  
pp. 757-771 ◽  
Author(s):  
Nimisha jain ◽  
Pradeep Kumar Singour
Keyword(s):  
Molecular Docking ◽  
Anticonvulsant Activity ◽  
Type A ◽  
Docking Study ◽  
Aminobutyric Acid ◽  
World Health ◽  
Maximal Electroshock ◽  
Gamma Aminobutyric Acid ◽  
Molecular Docking Study ◽  
Acid Type

Background: According to the World Health Organization, 50 million people worldwide are suffering from epilepsy, making it one of the most common neurological diseases globally. 2,3 disubstituted quinazolinone-4-one derivatives endowed with various pharmacological activity, particularly having anticonvulsant action. Objectives: The aim of this study was to synthesize 3-Substituted-2,3-Dihydro-2-thioxoquinazolin- 4-(1H)-one derivative and evaluate for anticonvulsant activity and neurotoxicity in order to find an efficient, compound with lesser side effects. Methods: A novel series of 3-[4-(2-amino-5, 6-dihydro-4(substituted phenyl)-4H-1, 3-oxazin /thiazin-6yl) phenyl]-2, 3-dihyro-2-thioxoquinazolin-4(1H)-one derivatives (4a-4p) were synthesized. The structures of the synthesized compounds were assigned on the basis of spectral data (UV, IR, 1HNMR, 13CNMR and MS) and performed anticonvulsant activity against maximal electroshock test and Subcutaneous Pentylenetetrazole model. Neurotoxicity was assessed using a rotarod apparatus test. The molecular docking study was performed to assess their binding affinities towards Gamma-Aminobutyric Acid type A receptor. A quantitative estimate of drug-likeness was also performed, which calculates the molecular properties and screen the molecules based on drug-likeness rules. Results: Compounds 4b, 4e, 4j and 4m have shown the highest anticonvulsant activity against tonic seizure with decreased mean duration of tonic hind leg extension of 8.31, 7.35, 8.61 and 8.99 s, respectively in maximal electroshock model and increased onset time clonic convulsion duration of 94.45, 96.65, 93.51 and 91.86 s in Subcutaneous Pentylenetetrazole model. Molecular docking study revealed a better binding affinity with Gamma-Aminobutyric Acid type A receptor. Conclusion: The compound 4b and 4e emerged out as the pilot molecule with a better anticonvulsant activity without any neurotoxicity. The obtained results showed that compounds 4b and 4e could be useful as a template for future design, optimization, and investigation to produce more active analogs.

[11C]Flumazenil Positron Emission Tomography Analyses of Brain Gamma-Aminobutyric Acid Type A Receptors in Angelman Syndrome

2008 ◽  
Vol 152 (4) ◽  
pp. 546-549.e3 ◽  
Author(s):  
Naoko Asahina ◽  
Tohru Shiga ◽  
Kiyoshi Egawa ◽  
Hideaki Shiraishi ◽  
Shinobu Kohsaka ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Angelman Syndrome ◽  
Type A ◽  
Emission Tomography ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Positron Emission ◽  
Acid Type

Autoradiographic Localization of the Gamma-Aminobutyric Acid Type A Receptor Agonist 3H-Muscimol in the Rat Superior Cervical Ganglion

Pharmacology ◽  
1992 ◽  
Vol 44 (2) ◽  
pp. 107-112 ◽  
Author(s):  
Francesco Amenta ◽  
Elena Bronzetti ◽  
Carlo Cavallotti ◽  
Laura Felici ◽  
Fabio Ferrante ◽  
...  
Keyword(s):  
Superior Cervical Ganglion ◽  
Receptor Agonist ◽  
Type A ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Acid Type ◽  
Cervical Ganglion

scholarly journals Modifications in Gamma-aminobutyric Acid type A Receptor Subunit Gene Expression During Macrophage Differentiation and Propofol Administration in THP-1 Cells

2021 ◽  
Author(s):  
Tsukasa Kochiyama ◽  
Izumi Kawagoe ◽  
Ai Yamaguchi ◽  
Masataka Fukuda ◽  
Masakazu Hayashida
Keyword(s):  
Gene Expression ◽  
Immune Cells ◽  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Subunit ◽  
Gamma Aminobutyric Acid ◽  
Subunit Gene ◽  
Macrophage Differentiation ◽  
Anesthetic Agents ◽  
Acid Type

Abstract Background: Gamma-aminobutyric acid type A (GABAA) receptors are thought to play a role in the functioning of the immune system. GABAA receptors have 19 types of subunits, the components of which determine their physiological functions. However, the subunits that are expressed in immune cells during inflammation have not been fully investigated. Recent reports have shown that anesthetic agents may affect the gene expression of GABAA receptors subunits in immune cells. Therefore, we aimed to investigate the changes in GABAA receptor subunit gene expression during macrophage differentiation and propofol administration in order to clarify the relationship between the expression of GABAA receptors and the immunomodulatory effect of propofol.Methods: Human acute monocytic leukemia (THP-1) cells were differentiated into macrophage-like cells (M0 THP-1); subsequently, M0 THP-1 cells were differentiated into inflammatory M1 macrophage-like cells (M1 THP-1). Propofol was administered during the differentiation into M1 THP-1 cells. Using reverse transcriptase polymerase chain reaction, we examined which GABAA receptor subunit genes were expressed and whether there were changes in the gene expression during macrophage differentiation and propofol administration in THP-1 cells.Results: The expression of the α1, α4, β1, β2, γ1, and γ2 subunits increased during differentiation into M0 THP-1 cells. The expression of the α1, α4, β1, β2, γ2, and δ subunits decreased and that of the γ1 subunit increased during differentiation into M1 THP-1 cells. The gene expression of the α1, α4, and β2 subunits increased upon administering propofol during differentiation into M1 THP-1 cells.Conclusions: The gene expression of GABAA receptor subunits changed during macrophage differentiation in THP-1 cells. The expressions of α1 and α4 increased following propofol administration during the differentiation into M1 THP-1 cells, which may indicate that the GABAA receptor is involved in the immunosuppressive effects of propofol. This study can help in the choice of anesthetic agents for proinflammatory conditions such as highly-invasive surgery.

Classic Benzodiazepines Modulate the Open–Close Equilibrium in α1β2γ2Lγ-Aminobutyric Acid Type A Receptors

2005 ◽  
Vol 102 (4) ◽  
pp. 783-792 ◽  
Author(s):  
Dirk Rüsch ◽  
Stuart A. Forman
Keyword(s):  
Gabaa Receptors ◽  
Sulfonic Acid ◽  
Site Occupancy ◽  
Type A ◽  
Aminobutyric Acid ◽  
Clinical Effects ◽  
Gamma Aminobutyric Acid ◽  
Wild Type ◽  
Acid Type ◽  
Benzodiazepine Site

Background Classic benzodiazepine agonists induce their clinical effects by binding to a site on gamma-aminobutyric acid type A (GABAA) receptors and enhancing receptor activity. There are conflicting data regarding whether the benzodiazepine site is allosterically coupled to gamma-aminobutyric acid binding versus the channel open-close (gating) equilibrium. The authors tested the hypothesis that benzodiazepine site ligands modulate alpha1beta2gamma2L GABAA receptor gating both in the absence of orthosteric agonists and when the orthosteric sites are occupied. Methods GABAA receptors were recombinantly expressed in Xenopus oocytes and studied using two-microelectrode voltage clamp electrophysiology. To test gating effects in the absence of orthosteric agonist, the authors used spontaneously active GABAA receptors containing a leucine-to-threonine mutation at residue 264 on the alpha1 subunit. To examine effects on gating when orthosteric sites were fully occupied, they activated wild-type receptors with high concentrations of a partial agonist, piperidine-4-sulfonic acid. Results In the absence of orthosteric agonists, the channel activity of alpha1L264Tbeta2gamma2L receptors was increased by diazepam and midazolam and reduced by the inverse benzodiazepine agonist FG7142. Flumazenil displayed very weak agonism and blocked midazolam from further activating mutant channels. In wild-type receptors activated with saturating concentrations of piperidine-4-sulfonic acid, midazolam increased maximal efficacy. Conclusions Independent of orthosteric site occupancy, classic benzodiazepines modulate the gating equilibrium in alpha1beta2gamma2L GABAA receptors and are therefore allosteric coagonists. A Monod-Wyman-Changeux coagonist gating model quantitatively predicts these effects, suggesting that benzodiazepines minimally alter orthosteric ligand binding.

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