SZR-104, a Novel Kynurenic Acid Analogue with High Permeability through the Blood–Brain Barrier
By being an antagonist of glutamate and other receptors, kynurenic acid serves as an endogenous neuroprotectant in several pathologies of the brain. Unfortunately, systemic administration of kynurenic acid is hindered by its low permeability through the blood–brain barrier. One possibility to overco...
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| Format: | Article |
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MDPI AG
2021-01-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/1/61 |
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| author | Kinga Molnár Bálint Lőrinczi Csilla Fazakas István Szatmári Ferenc Fülöp Noémi Kmetykó Róbert Berkecz István Ilisz István A. Krizbai Imola Wilhelm László Vécsei |
| author_facet | Kinga Molnár Bálint Lőrinczi Csilla Fazakas István Szatmári Ferenc Fülöp Noémi Kmetykó Róbert Berkecz István Ilisz István A. Krizbai Imola Wilhelm László Vécsei |
| author_sort | Kinga Molnár |
| collection | DOAJ |
| description | By being an antagonist of glutamate and other receptors, kynurenic acid serves as an endogenous neuroprotectant in several pathologies of the brain. Unfortunately, systemic administration of kynurenic acid is hindered by its low permeability through the blood–brain barrier. One possibility to overcome this problem is to use analogues with similar biological activity as kynurenic acid, but with an increased permeability through the blood–brain barrier. We synthesized six novel aminoalkylated amide derivatives of kynurenic acid, among which SZR-104 (<i>N</i>-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-hydroxyquinoline-2-carboxamide) proved to have the highest permeability through an in vitro blood–brain barrier model. In addition, permeability of SZR-104 was significantly higher than that of kynurenic acid, xanthurenic acid and 39B, a quinolone derivative/xanthurenic acid analogue. Since peripherally administered SZR-104 is able to inhibit epileptiform activity in the brain, we conclude that SZR-104 is a promising kynurenic acid analogue with good penetrability into the central nervous system. |
| first_indexed | 2024-03-10T13:27:48Z |
| format | Article |
| id | doaj.art-2e52001ba180480f8b5df287d84d1ffa |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T13:27:48Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-2e52001ba180480f8b5df287d84d1ffa2023-11-21T08:38:28ZengMDPI AGPharmaceutics1999-49232021-01-011316110.3390/pharmaceutics13010061SZR-104, a Novel Kynurenic Acid Analogue with High Permeability through the Blood–Brain BarrierKinga Molnár0Bálint Lőrinczi1Csilla Fazakas2István Szatmári3Ferenc Fülöp4Noémi Kmetykó5Róbert Berkecz6István Ilisz7István A. Krizbai8Imola Wilhelm9László Vécsei10Institute of Biophysics, Biological Research Centre, 6726 Szeged, HungaryInstitute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, 6720 Szeged, HungaryInstitute of Biophysics, Biological Research Centre, 6726 Szeged, HungaryInstitute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, 6720 Szeged, HungaryInstitute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, 6720 Szeged, HungaryInstitute of Pharmaceutical Analysis, Interdisciplinary Excellence Center, University of Szeged, 6720 Szeged, HungaryInstitute of Pharmaceutical Analysis, Interdisciplinary Excellence Center, University of Szeged, 6720 Szeged, HungaryInstitute of Pharmaceutical Analysis, Interdisciplinary Excellence Center, University of Szeged, 6720 Szeged, HungaryInstitute of Biophysics, Biological Research Centre, 6726 Szeged, HungaryInstitute of Biophysics, Biological Research Centre, 6726 Szeged, HungaryDepartment of Neurology, Interdisciplinary Excellence Center, University of Szeged, 6725 Szeged, HungaryBy being an antagonist of glutamate and other receptors, kynurenic acid serves as an endogenous neuroprotectant in several pathologies of the brain. Unfortunately, systemic administration of kynurenic acid is hindered by its low permeability through the blood–brain barrier. One possibility to overcome this problem is to use analogues with similar biological activity as kynurenic acid, but with an increased permeability through the blood–brain barrier. We synthesized six novel aminoalkylated amide derivatives of kynurenic acid, among which SZR-104 (<i>N</i>-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-hydroxyquinoline-2-carboxamide) proved to have the highest permeability through an in vitro blood–brain barrier model. In addition, permeability of SZR-104 was significantly higher than that of kynurenic acid, xanthurenic acid and 39B, a quinolone derivative/xanthurenic acid analogue. Since peripherally administered SZR-104 is able to inhibit epileptiform activity in the brain, we conclude that SZR-104 is a promising kynurenic acid analogue with good penetrability into the central nervous system.https://www.mdpi.com/1999-4923/13/1/61aminoalkylated amide derivativesblood–brain barrier (BBB)in vitro modelkynurenic acid (KYNA)permeabilitySZR-104 |
| spellingShingle | Kinga Molnár Bálint Lőrinczi Csilla Fazakas István Szatmári Ferenc Fülöp Noémi Kmetykó Róbert Berkecz István Ilisz István A. Krizbai Imola Wilhelm László Vécsei SZR-104, a Novel Kynurenic Acid Analogue with High Permeability through the Blood–Brain Barrier Pharmaceutics aminoalkylated amide derivatives blood–brain barrier (BBB) in vitro model kynurenic acid (KYNA) permeability SZR-104 |
| title | SZR-104, a Novel Kynurenic Acid Analogue with High Permeability through the Blood–Brain Barrier |
| title_full | SZR-104, a Novel Kynurenic Acid Analogue with High Permeability through the Blood–Brain Barrier |
| title_fullStr | SZR-104, a Novel Kynurenic Acid Analogue with High Permeability through the Blood–Brain Barrier |
| title_full_unstemmed | SZR-104, a Novel Kynurenic Acid Analogue with High Permeability through the Blood–Brain Barrier |
| title_short | SZR-104, a Novel Kynurenic Acid Analogue with High Permeability through the Blood–Brain Barrier |
| title_sort | szr 104 a novel kynurenic acid analogue with high permeability through the blood brain barrier |
| topic | aminoalkylated amide derivatives blood–brain barrier (BBB) in vitro model kynurenic acid (KYNA) permeability SZR-104 |
| url | https://www.mdpi.com/1999-4923/13/1/61 |
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