Preferential Synaptic Type of GABA-A Receptor Ligands Enhancing Neuronal Survival and Facilitating Functional Recovery After Ischemic Stroke

  • J Med Chem. 2024 Dec 26;67(24):21859-21889. doi: 10.1021/acs.jmedchem.4c01578.
Barbara Mordyl  1 ,  Nikola Fajkis-Zajączkowska  2 ,  Katarzyna Szafrańska  2  3 ,  Agata Siwek  1  4 ,  Monika Głuch-Lutwin  1 ,  Paweł Żmudzki  2  4 ,  Jakub Jończyk  2 ,  Tadeusz Karcz  5 ,  Karolina Słoczyńska  6 ,  Elżbieta Pękala  6 ,  Bartosz Pomierny  4  7 ,  Weronika Krzyżanowska  7 ,  Jakub Jurczyk  3  8 ,  Alicja Skórkowska  4  7 ,  Aleksandra Sałach  9 ,  Magdalena Jastrzębska-Więsek  9 ,  Maria Walczak  8 ,  Maciej Tadeusz Gawlik  8 ,  Magdalena Smolik  8 ,  Marcin Kolaczkowski  2 ,  Monika Marcinkowska  2  4
Affiliations
  • 1. Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
  • 2. Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
  • 3. Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, 16 Lazarza St., Krakow 31-530, Poland.
  • 4. Center for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Skawińska 8, Krakow 31-066, Poland.
  • 5. Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
  • 6. Department of Pharmaceutical Biochemistry, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
  • 7. Department of Toxicological Biochemistry, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
  • 8. Department of Toxicology, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
  • 9. Department of Clinical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
PMID: 39668673 DOI: 10.1021/acs.jmedchem.4c01578
Abstract

Selective enhancement of synaptic GABA signaling mediated by GABA-A receptors has been previously reported to promote functional recovery after ischemic stroke, while tonic GABA signaling has been detrimental. To identify agents that enhance synaptic signaling, we synthesized GABA-A ligands based on three chemotypes with affinity values pKi= 6.44-8.32. Representative compounds showed a preference in functional responses toward synaptic type of GABA-A receptors, compared to the extrasynaptic ones. In a cellular ischemia model (OGD), selected compounds showed the potential to improve neuronal recovery. The selected lead, compound 4, demonstrated the ability to reduce mitochondrial dysfunction, regulate intracellular calcium levels, decrease Caspase 3 levels, and promote neurite outgrowth in in vitro assays. In an animal model, compound 4 enhanced motor recovery and showed neuroprotective activity by reducing infarct volume and decreasing poststroke acidosis. These findings underscore the value of selective ligands modulating synaptic GABA-A receptors in promoting recovery from ischemic stroke.

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