Exploring GABAA receptor modulation through integrated synthesis, bioactivity, and computational approach of 1,2,4-triazine derivatives.
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| Title: | Exploring GABAA receptor modulation through integrated synthesis, bioactivity, and computational approach of 1,2,4-triazine derivatives. |
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| Authors: | Singh, Hariram1,2 (AUTHOR) hari.niper2010@gmail.com, Manaithiya, Ajay3 (AUTHOR), Pathak, Devender4 (AUTHOR), Shakeel, Faiyaz1,5 (AUTHOR) fsahmad@ksu.edu.sa |
| Source: | Journal of Molecular Structure. Mar2025, Vol. 1325, pN.PAG-N.PAG. 1p. |
| Subjects: | Drug design, Density functional theory, Hydrophobic interactions, Ligand binding (Biochemistry), Molecular dynamics, Triazine derivatives |
| Abstract: | • Novel 1,2,4-triazine derivatives as potential AEDs have been explored. • Designed, synthesized, and evaluated the anticonvulsant activity of derivatives HRS1-HRS42. • Compound HRS9 significantly altered neurotransmitter levels, increasing GABA and reducing glutamate. • Docking studies demonstrated effective binding of compounds to alpha subunit sites within the GABA A receptor complex. Epilepsy, a prevalent neurological disorder, is often treated with antiepileptic drugs (AEDs), which frequently suffer from toxicity, intolerance, and limited efficacy. Addressing these challenges, our study explores novel 1,2,4-triazine derivatives as potential AEDs. We designed, synthesized, and evaluated the anticonvulsant activity of derivatives HRS1-HRS42 in vivo , notably in the maximal electroshock (MES) and Strychnine-induced convulsion models. Compounds HRS4 and HRS9 demonstrated significant anticonvulsive activity, with HRS9 exhibiting a higher effective dose (ED 50 of 28.6 mg/kg) compared to traditional drugs like phenytoin (9.5 mg/kg) and carbamazepine (8.8 mg/kg). Additionally, these compounds displayed antioxidant properties through DPPH and FRAP assays. Compound HRS9 significantly altered neurotransmitter levels, increasing GABA and reducing glutamate in the brain tissue and cortex, which correlates with reduced seizure activity. Acute safety studies confirmed the safety of compound HRS9, with no significant pathological changes observed in histopathological analyses. Molecular interactions were analyzed using Field-based Gaussian 3D-QSAR, highlighting the importance of steric and hydrophobic effects in molecule design. Furthermore, docking studies demonstrated effective binding of compounds to alpha subunit sites within the GABA A receptor complex, corroborating the biochemical efficacy observed. Molecular dynamics in aqueous medium, and lipid bilayer environment and density functional theory further provided insights into the stability of ligand binding and electronic properties, critical for rational drug design. This comprehensive evaluation not only underscores the potential of 1,2,4-triazine derivatives in advancing the design of new molecules against epilepsy but also sets the stage for subsequent clinical studies to further explore their therapeutic viability. [Display omitted] [ABSTRACT FROM AUTHOR] |
| Copyright of Journal of Molecular Structure is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
| FullText | Text: Availability: 0 |
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| Header | DbId: egs DbLabel: Engineering Source An: 182299714 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Exploring GABAA receptor modulation through integrated synthesis, bioactivity, and computational approach of 1,2,4-triazine derivatives. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Singh%2C+Hariram%22">Singh, Hariram</searchLink><relatesTo>1,2</relatesTo> (AUTHOR)<i> hari.niper2010@gmail.com</i><br /><searchLink fieldCode="AR" term="%22Manaithiya%2C+Ajay%22">Manaithiya, Ajay</searchLink><relatesTo>3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Pathak%2C+Devender%22">Pathak, Devender</searchLink><relatesTo>4</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Shakeel%2C+Faiyaz%22">Shakeel, Faiyaz</searchLink><relatesTo>1,5</relatesTo> (AUTHOR)<i> fsahmad@ksu.edu.sa</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Journal+of+Molecular+Structure%22">Journal of Molecular Structure</searchLink>. Mar2025, Vol. 1325, pN.PAG-N.PAG. 1p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Drug+design%22">Drug design</searchLink><br /><searchLink fieldCode="DE" term="%22Density+functional+theory%22">Density functional theory</searchLink><br /><searchLink fieldCode="DE" term="%22Hydrophobic+interactions%22">Hydrophobic interactions</searchLink><br /><searchLink fieldCode="DE" term="%22Ligand+binding+%28Biochemistry%29%22">Ligand binding (Biochemistry)</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+dynamics%22">Molecular dynamics</searchLink><br /><searchLink fieldCode="DE" term="%22Triazine+derivatives%22">Triazine derivatives</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: • Novel 1,2,4-triazine derivatives as potential AEDs have been explored. • Designed, synthesized, and evaluated the anticonvulsant activity of derivatives HRS1-HRS42. • Compound HRS9 significantly altered neurotransmitter levels, increasing GABA and reducing glutamate. • Docking studies demonstrated effective binding of compounds to alpha subunit sites within the GABA A receptor complex. Epilepsy, a prevalent neurological disorder, is often treated with antiepileptic drugs (AEDs), which frequently suffer from toxicity, intolerance, and limited efficacy. Addressing these challenges, our study explores novel 1,2,4-triazine derivatives as potential AEDs. We designed, synthesized, and evaluated the anticonvulsant activity of derivatives HRS1-HRS42 in vivo , notably in the maximal electroshock (MES) and Strychnine-induced convulsion models. Compounds HRS4 and HRS9 demonstrated significant anticonvulsive activity, with HRS9 exhibiting a higher effective dose (ED 50 of 28.6 mg/kg) compared to traditional drugs like phenytoin (9.5 mg/kg) and carbamazepine (8.8 mg/kg). Additionally, these compounds displayed antioxidant properties through DPPH and FRAP assays. Compound HRS9 significantly altered neurotransmitter levels, increasing GABA and reducing glutamate in the brain tissue and cortex, which correlates with reduced seizure activity. Acute safety studies confirmed the safety of compound HRS9, with no significant pathological changes observed in histopathological analyses. Molecular interactions were analyzed using Field-based Gaussian 3D-QSAR, highlighting the importance of steric and hydrophobic effects in molecule design. Furthermore, docking studies demonstrated effective binding of compounds to alpha subunit sites within the GABA A receptor complex, corroborating the biochemical efficacy observed. Molecular dynamics in aqueous medium, and lipid bilayer environment and density functional theory further provided insights into the stability of ligand binding and electronic properties, critical for rational drug design. This comprehensive evaluation not only underscores the potential of 1,2,4-triazine derivatives in advancing the design of new molecules against epilepsy but also sets the stage for subsequent clinical studies to further explore their therapeutic viability. [Display omitted] [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Journal of Molecular Structure is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1016/j.molstruc.2024.140924 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 1 StartPage: N.PAG Subjects: – SubjectFull: Drug design Type: general – SubjectFull: Density functional theory Type: general – SubjectFull: Hydrophobic interactions Type: general – SubjectFull: Ligand binding (Biochemistry) Type: general – SubjectFull: Molecular dynamics Type: general – SubjectFull: Triazine derivatives Type: general Titles: – TitleFull: Exploring GABAA receptor modulation through integrated synthesis, bioactivity, and computational approach of 1,2,4-triazine derivatives. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Singh, Hariram – PersonEntity: Name: NameFull: Manaithiya, Ajay – PersonEntity: Name: NameFull: Pathak, Devender – PersonEntity: Name: NameFull: Shakeel, Faiyaz IsPartOfRelationships: – BibEntity: Dates: – D: 15 M: 03 Text: Mar2025 Type: published Y: 2025 Identifiers: – Type: issn-print Value: 00222860 Numbering: – Type: volume Value: 1325 Titles: – TitleFull: Journal of Molecular Structure Type: main |
| ResultId | 1 |
