Phenylalanine-Based AMPA Receptor Antagonist as the Anticonvulsant Agent with Neuroprotective Activity—In Vitro and In Vivo Studies
Trying to meet the multitarget-directed ligands strategy, a series of previously described aryl-substituted phenylalanine derivatives, reported as competitive antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, were screened in vitro for their free-radical scavengin...
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| Format: | Article |
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MDPI AG
2022-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/3/875 |
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| author | Gniewomir Latacz Kinga Sałat Anna Furgała-Wojas Adrian Martyniak Agnieszka Olejarz-Maciej Ewelina Honkisz-Orzechowska Ewa Szymańska |
| author_facet | Gniewomir Latacz Kinga Sałat Anna Furgała-Wojas Adrian Martyniak Agnieszka Olejarz-Maciej Ewelina Honkisz-Orzechowska Ewa Szymańska |
| author_sort | Gniewomir Latacz |
| collection | DOAJ |
| description | Trying to meet the multitarget-directed ligands strategy, a series of previously described aryl-substituted phenylalanine derivatives, reported as competitive antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, were screened in vitro for their free-radical scavenging and antioxidant capacity in two different assays: ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity fluorescent (ORAC-FL) assays. The most active antioxidants <b>1</b> and <b>8</b> were further examined to evaluate their neuroprotective properties in vitro. In this study, compound <b>1</b> showed a significant neuroprotective effect against the neurotoxin 6-hydroxydopamine in neuroblastoma SH-SY5Y and IMR-32 cell lines. Both compounds also showed prevention from high levels of reactive oxygen species (ROS) in SH-SY5Y cells. Furthermore, the desired monoamine oxidase B (MAO-B) inhibition effect (IC<sub>50</sub> = 278 ± 29 nM) for <b>1</b> was determined. No toxic effects up to 100 µM of <b>1</b> and <b>8</b> against neuroblastoma cells were observed. Furthermore, in vivo studies showed that compound <b>1</b> demonstrated significant anticonvulsant potential in 6-Hz test, but in neuropathic pain models its antiallodynic and antihyperalgesic properties were not observed. Concluding, the compound <b>1</b> seems to be of higher importance as a new phenylalanine-based lead candidate due to its confirmed promise in in vitro and in vivo anticonvulsant activity. |
| first_indexed | 2024-03-09T23:28:04Z |
| format | Article |
| id | doaj.art-30c4052d21b04e6595507df4b292cee4 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T23:28:04Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-30c4052d21b04e6595507df4b292cee42023-11-23T17:13:51ZengMDPI AGMolecules1420-30492022-01-0127387510.3390/molecules27030875Phenylalanine-Based AMPA Receptor Antagonist as the Anticonvulsant Agent with Neuroprotective Activity—In Vitro and In Vivo StudiesGniewomir Latacz0Kinga Sałat1Anna Furgała-Wojas2Adrian Martyniak3Agnieszka Olejarz-Maciej4Ewelina Honkisz-Orzechowska5Ewa Szymańska6Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, PolandDepartment of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, PolandDepartment of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, PolandDepartment of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, PolandDepartment of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, PolandDepartment of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, PolandDepartment of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, PolandTrying to meet the multitarget-directed ligands strategy, a series of previously described aryl-substituted phenylalanine derivatives, reported as competitive antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, were screened in vitro for their free-radical scavenging and antioxidant capacity in two different assays: ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity fluorescent (ORAC-FL) assays. The most active antioxidants <b>1</b> and <b>8</b> were further examined to evaluate their neuroprotective properties in vitro. In this study, compound <b>1</b> showed a significant neuroprotective effect against the neurotoxin 6-hydroxydopamine in neuroblastoma SH-SY5Y and IMR-32 cell lines. Both compounds also showed prevention from high levels of reactive oxygen species (ROS) in SH-SY5Y cells. Furthermore, the desired monoamine oxidase B (MAO-B) inhibition effect (IC<sub>50</sub> = 278 ± 29 nM) for <b>1</b> was determined. No toxic effects up to 100 µM of <b>1</b> and <b>8</b> against neuroblastoma cells were observed. Furthermore, in vivo studies showed that compound <b>1</b> demonstrated significant anticonvulsant potential in 6-Hz test, but in neuropathic pain models its antiallodynic and antihyperalgesic properties were not observed. Concluding, the compound <b>1</b> seems to be of higher importance as a new phenylalanine-based lead candidate due to its confirmed promise in in vitro and in vivo anticonvulsant activity.https://www.mdpi.com/1420-3049/27/3/875AMPA antagonistphenylalanineneuroprotectionantioxidant activityFRAPORAC-FL |
| spellingShingle | Gniewomir Latacz Kinga Sałat Anna Furgała-Wojas Adrian Martyniak Agnieszka Olejarz-Maciej Ewelina Honkisz-Orzechowska Ewa Szymańska Phenylalanine-Based AMPA Receptor Antagonist as the Anticonvulsant Agent with Neuroprotective Activity—In Vitro and In Vivo Studies Molecules AMPA antagonist phenylalanine neuroprotection antioxidant activity FRAP ORAC-FL |
| title | Phenylalanine-Based AMPA Receptor Antagonist as the Anticonvulsant Agent with Neuroprotective Activity—In Vitro and In Vivo Studies |
| title_full | Phenylalanine-Based AMPA Receptor Antagonist as the Anticonvulsant Agent with Neuroprotective Activity—In Vitro and In Vivo Studies |
| title_fullStr | Phenylalanine-Based AMPA Receptor Antagonist as the Anticonvulsant Agent with Neuroprotective Activity—In Vitro and In Vivo Studies |
| title_full_unstemmed | Phenylalanine-Based AMPA Receptor Antagonist as the Anticonvulsant Agent with Neuroprotective Activity—In Vitro and In Vivo Studies |
| title_short | Phenylalanine-Based AMPA Receptor Antagonist as the Anticonvulsant Agent with Neuroprotective Activity—In Vitro and In Vivo Studies |
| title_sort | phenylalanine based ampa receptor antagonist as the anticonvulsant agent with neuroprotective activity in vitro and in vivo studies |
| topic | AMPA antagonist phenylalanine neuroprotection antioxidant activity FRAP ORAC-FL |
| url | https://www.mdpi.com/1420-3049/27/3/875 |
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