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

Autor:	Mordyl B; Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Fajkis-Zajączkowska N; Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Szafrańska K; Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.; Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, 16 Lazarza St., Krakow 31-530, Poland., Siwek A; Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.; Center for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Skawińska 8, Krakow 31-066, Poland., Głuch-Lutwin M; Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Żmudzki P; Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.; Center for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Skawińska 8, Krakow 31-066, Poland., Jończyk J; Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Karcz T; Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Słoczyńska K; Department of Pharmaceutical Biochemistry, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Pękala E; Department of Pharmaceutical Biochemistry, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Pomierny B; Center for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Skawińska 8, Krakow 31-066, Poland.; Department of Toxicological Biochemistry, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Krzyżanowska W; Department of Toxicological Biochemistry, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Jurczyk J; Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, 16 Lazarza St., Krakow 31-530, Poland.; Department of Toxicology, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Skórkowska A; Center for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Skawińska 8, Krakow 31-066, Poland.; Department of Toxicological Biochemistry, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Sałach A; Department of Clinical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Jastrzębska-Więsek M; Department of Clinical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Walczak M; Department of Toxicology, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Gawlik MT; Department of Toxicology, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Smolik M; Department of Toxicology, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Kolaczkowski M; Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland., Marcinkowska M; Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.; Center for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Skawińska 8, Krakow 31-066, Poland.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Dec 26; Vol. 67 (24), pp. 21859-21889. Date of Electronic Publication: 2024 Dec 12.
DOI:	10.1021/acs.jmedchem.4c01578
Abstrakt:	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 p K i = 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.
Databáze:	MEDLINE
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