Stereospecific Inhibition of Ethanol Potentiation on Glycine Receptor by M554 Stereoisomers

Pilar A. Vásquez; Loreto San Martín; Yenifer Argel; Camila Riquelme; Josefa Torres; Felipe Vidal; Francisca Cayuman; Patricio Castro; Jorge Fuentealba; Gustavo Moraga-Cid; Gonzalo Yevenes; Chunyang Jin; Verónica A. Jiménez; Leonardo Guzmán

doi:10.1021/acs.jcim.0c00943

Stereospecific Inhibition of Ethanol Potentiation on Glycine Receptor by M554 Stereoisomers

Pilar A. Vásquez, Loreto San Martín, Yenifer Argel, Camila Riquelme, Josefa Torres, Felipe Vidal, Francisca Cayuman, Patricio Castro, Jorge Fuentealba, Gustavo Moraga-Cid, Gonzalo Yevenes, Chunyang Jin, Verónica A. Jiménez, Leonardo Guzmán

Research output: Contribution to journal › Article › peer-review

Abstract

Blocking the interaction between the Gβγprotein and the glycine receptor (GlyR) has emerged as a promising pharmacological strategy to treat acute alcohol intoxication by inhibiting ethanol potentiation on GlyR. M554 is a recently discovered small molecule capable of binding to Gβγwith potent in vitro and in vivo inhibitory activity. This compound has been tested as a mixture of diastereomers, and no information is available concerning the stereospecific activity of each species, which is critical to pursue efforts on lead optimization and drug development. In this work, we explored the differential activity of four M554 stereoisomers by in silico molecular dynamics simulations and electrophysiological experiments. Our results revealed that the (R,R)-M554 stereoisomer is a promising lead compound that inhibits ethanol potentiation of GlyR.

Original language	English
Journal	Journal of Chemical Information and Modeling
DOIs	https://doi.org/10.1021/acs.jcim.0c00943
Publication status	Accepted/In press - 2020

ASJC Scopus subject areas

General Chemistry
General Chemical Engineering
Computer Science Applications
Library and Information Sciences

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Vásquez, P. A., San Martín, L., Argel, Y., Riquelme, C., Torres, J., Vidal, F., Cayuman, F., Castro, P., Fuentealba, J., Moraga-Cid, G., Yevenes, G., Jin, C., Jiménez, V. A., & Guzmán, L. (Accepted/In press). Stereospecific Inhibition of Ethanol Potentiation on Glycine Receptor by M554 Stereoisomers. Journal of Chemical Information and Modeling. https://doi.org/10.1021/acs.jcim.0c00943

@article{7a5ad617865245e78d37cf305f8f10c1,

title = "Stereospecific Inhibition of Ethanol Potentiation on Glycine Receptor by M554 Stereoisomers",

abstract = "Blocking the interaction between the Gβγprotein and the glycine receptor (GlyR) has emerged as a promising pharmacological strategy to treat acute alcohol intoxication by inhibiting ethanol potentiation on GlyR. M554 is a recently discovered small molecule capable of binding to Gβγwith potent in vitro and in vivo inhibitory activity. This compound has been tested as a mixture of diastereomers, and no information is available concerning the stereospecific activity of each species, which is critical to pursue efforts on lead optimization and drug development. In this work, we explored the differential activity of four M554 stereoisomers by in silico molecular dynamics simulations and electrophysiological experiments. Our results revealed that the (R,R)-M554 stereoisomer is a promising lead compound that inhibits ethanol potentiation of GlyR.",

author = "V{\'a}squez, {Pilar A.} and {San Mart{\'i}n}, Loreto and Yenifer Argel and Camila Riquelme and Josefa Torres and Felipe Vidal and Francisca Cayuman and Patricio Castro and Jorge Fuentealba and Gustavo Moraga-Cid and Gonzalo Yevenes and Chunyang Jin and Jim{\'e}nez, {Ver{\'o}nica A.} and Leonardo Guzm{\'a}n",

note = "Funding Information: We would like to thank Laurie Aguayo and Carolina Benitez for valuable discussion and technical assistance. This work was supported by FONDECYT under Grant 1170853 (L.G.). Computational modeling resources were provided by FONDECYT under Grant 1160060 (V.A.J.). Publisher Copyright: {\textcopyright} 2020 American Chemical Society. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

doi = "10.1021/acs.jcim.0c00943",

language = "English",

journal = "Journal of Chemical Information and Modeling",

issn = "1549-9596",

publisher = "American Chemical Society",

}

TY - JOUR

T1 - Stereospecific Inhibition of Ethanol Potentiation on Glycine Receptor by M554 Stereoisomers

AU - Vásquez, Pilar A.

AU - San Martín, Loreto

AU - Argel, Yenifer

AU - Riquelme, Camila

AU - Torres, Josefa

AU - Vidal, Felipe

AU - Cayuman, Francisca

AU - Castro, Patricio

AU - Fuentealba, Jorge

AU - Moraga-Cid, Gustavo

AU - Yevenes, Gonzalo

AU - Jin, Chunyang

AU - Jiménez, Verónica A.

AU - Guzmán, Leonardo

N1 - Funding Information: We would like to thank Laurie Aguayo and Carolina Benitez for valuable discussion and technical assistance. This work was supported by FONDECYT under Grant 1170853 (L.G.). Computational modeling resources were provided by FONDECYT under Grant 1160060 (V.A.J.). Publisher Copyright: © 2020 American Chemical Society. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020

Y1 - 2020

N2 - Blocking the interaction between the Gβγprotein and the glycine receptor (GlyR) has emerged as a promising pharmacological strategy to treat acute alcohol intoxication by inhibiting ethanol potentiation on GlyR. M554 is a recently discovered small molecule capable of binding to Gβγwith potent in vitro and in vivo inhibitory activity. This compound has been tested as a mixture of diastereomers, and no information is available concerning the stereospecific activity of each species, which is critical to pursue efforts on lead optimization and drug development. In this work, we explored the differential activity of four M554 stereoisomers by in silico molecular dynamics simulations and electrophysiological experiments. Our results revealed that the (R,R)-M554 stereoisomer is a promising lead compound that inhibits ethanol potentiation of GlyR.

AB - Blocking the interaction between the Gβγprotein and the glycine receptor (GlyR) has emerged as a promising pharmacological strategy to treat acute alcohol intoxication by inhibiting ethanol potentiation on GlyR. M554 is a recently discovered small molecule capable of binding to Gβγwith potent in vitro and in vivo inhibitory activity. This compound has been tested as a mixture of diastereomers, and no information is available concerning the stereospecific activity of each species, which is critical to pursue efforts on lead optimization and drug development. In this work, we explored the differential activity of four M554 stereoisomers by in silico molecular dynamics simulations and electrophysiological experiments. Our results revealed that the (R,R)-M554 stereoisomer is a promising lead compound that inhibits ethanol potentiation of GlyR.

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DO - 10.1021/acs.jcim.0c00943

M3 - Article

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SN - 1549-9596

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

ER -

Stereospecific Inhibition of Ethanol Potentiation on Glycine Receptor by M554 Stereoisomers

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