New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model.

Date

2018-02-22

Author

Konstantinović, J
Kiriş, Erkan
Kota, KP
Kugelman-Tonos, J
Videnović, M
Cazares, LH
Terzić, Jovanović
Verbić, TŽ
Andjelković, B
Duplantier, AJ
Bavari, S
Šolaja, BA

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The synthesis and inhibitory potencies against botulinum neurotoxin serotype A light chain (BoNT/A LC) using in vitro HPLC based enzymatic assay for various steroidal, benzothiophene, thiophene, and adamantane 4-aminoquinoline derivatives are described. In addition, the compounds were evaluated for the activity against BoNT/A holotoxin in mouse embryonic stem cell derived motor neurons. Steroidal derivative 16 showed remarkable protection (up to 89% of uncleaved SNAP-25) even when administered 30 min postintoxication. This appears to be the first example of LC inhibitors antagonizing BoNT intoxication in mouse embryonic stem cell derived motor neurons (mES-MNs) in a postexposure model. Oral administration of 16 was well tolerated in the mouse up to 600 mg/kg, q.d. Although adequate unbound drug levels were not achieved at this dose, the favorable in vitro ADMET results strongly support further work in this series.

Subject Keywords

Molecular Medicine, Drug Discovery

URI

https://hdl.handle.net/11511/38503

Journal

Journal of medicinal chemistry

DOI

https://doi.org/10.1021/acs.jmedchem.7b01710

Collections

Department of Biology, Article

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Citation Formats

J. Konstantinović et al., “New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model.,” Journal of medicinal chemistry, pp. 1595–1608, 2018, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/38503.