SZR-104, a Novel Kynurenic Acid Analogue with High Permeability through the Blood–Brain Barrier
Kinga Molnár,
Bálint Lőrinczi,
Csilla Fazakas,
István Szatmári,
Ferenc Fülöp,
Noémi Kmetykó,
Róbert Berkecz,
István Ilisz,
István A. Krizbai,
Imola Wilhelm,
László Vécsei
Affiliations
Kinga Molnár
Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary
Bálint Lőrinczi
Institute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, 6720 Szeged, Hungary
Csilla Fazakas
Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary
István Szatmári
Institute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, 6720 Szeged, Hungary
Ferenc Fülöp
Institute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, 6720 Szeged, Hungary
Noémi Kmetykó
Institute of Pharmaceutical Analysis, Interdisciplinary Excellence Center, University of Szeged, 6720 Szeged, Hungary
Róbert Berkecz
Institute of Pharmaceutical Analysis, Interdisciplinary Excellence Center, University of Szeged, 6720 Szeged, Hungary
István Ilisz
Institute of Pharmaceutical Analysis, Interdisciplinary Excellence Center, University of Szeged, 6720 Szeged, Hungary
István A. Krizbai
Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary
Imola Wilhelm
Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary
László Vécsei
Department of Neurology, Interdisciplinary Excellence Center, University of Szeged, 6725 Szeged, Hungary
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 (N-(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.
