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Plasminogen binding inhibitors demonstrate unwanted activities on GABAA and glycine receptors in human iPSC derived neurons
AstraZeneca, Mölndal, Sweden.
AstraZeneca, Mölndal, Sweden / Karolinska Institutet, Stockholm, Sweden.
Emeriti Bio, AZ Bioventure Hub, Mölndal, Sweden.
Emeriti Bio, AZ Bioventure Hub, Mölndal, Sweden.
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2018 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 681, p. 37-43, article id S0304-3940(18)30351-3Article in journal (Refereed) Published
Abstract [en]

Plasminogen binding inhibitors (PBIs) reduce the risk of bleeding in hemorrhagic conditions. However, generic PBIs are also associated with an increased risk of seizures, an adverse effect linked to unwanted activities towards inhibitory neuronal receptors. Development of novel PBIs serve to remove compounds with such properties, but progress is limited by a lack of higher throughput methods with human translatability. Herein we apply human induced pluripotent stem cell (hiPSC) derived neurons in combination with dynamic mass redistribution (DMR) technology to demonstrate robust and reproducible modulation of both GABAA and glycine receptors. These cells respond to GABA (EC50 0.33 ± 0.18 μM), glycine (EC50 11.0 ± 3.7 μM) and additional ligands in line with previous reports from patch clamp technologies. Additionally, we identify and characterize a competitive antagonistic behavior of the prototype inhibitor and drug tranexamic acid (TXA). Finally, we demonstrate proof of concept for effective counter-screening of lead series compounds towards unwanted GABAAreceptor activities. No activity was observed for a previously identified PBI candidate drug, AZD6564, whereas a discontinued analog, AZ13267257, could be characterized as a potent GABAA receptor agonist.

Place, publisher, year, edition, pages
2018. Vol. 681, p. 37-43, article id S0304-3940(18)30351-3
Keywords [en]
Drug screening, Dynamic mass redistribution, GABA(A) receptor, Glycine receptor, Pharmacology, hiPSC derived neurons
National Category
Cell Biology
Research subject
Bioinformatics
Identifiers
URN: urn:nbn:se:his:diva-15263DOI: 10.1016/j.neulet.2018.05.018ISI: 000442191200008PubMedID: 29758302Scopus ID: 2-s2.0-85047397711OAI: oai:DiVA.org:his-15263DiVA, id: diva2:1212838
Available from: 2018-06-04 Created: 2018-06-04 Last updated: 2018-09-11Bibliographically approved

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Delsing, Louise

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