Pharmacological characterization and binding modes of novel racemic and optically active phenylalanine-based antagonists of AMPA receptors

Ewa Szymańska; Birgitte Nielsen; Tommy Nørskov Johansen; Anna Maria Cuñado Moral; Darryl S Pickering; Katarzyna Szczepańska; Anna Mickowska; Katarzyna Kieć-Kononowicz

doi:10.1016/j.ejmech.2017.07.007

Pharmacological characterization and binding modes of novel racemic and optically active phenylalanine-based antagonists of AMPA receptors

Ewa Szymańska, Birgitte Nielsen, Tommy Nørskov Johansen, Anna Maria Cuñado Moral, Darryl S Pickering, Katarzyna Szczepańska, Anna Mickowska, Katarzyna Kieć-Kononowicz

Abstract

In order to map out molecular determinants for the competitive blockade of AMPA receptor subtypes, a series of racemic aryl-substituted phenylalanines was synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors. Most of the compounds showed micromolar affinity and preference for AMPA receptors. Individual stereoisomers of selected compounds were further evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. The most potent compound, (–)-2-amino-3-(6-chloro-2',5'-dihydroxy-5-nitro-[1,1'-biphenyl]-3-yl)propanoic acid, the expected R-isomer showing K_i of 1.71 µM at the GluA2 subtype, was found to competitively antagonize GluA2(Q)_i receptors in TEVC electrophysiological experiments (K_b = 2.13 µM). Molecular docking experiments allowed us to compare two alternative antagonist binding modes for the synthesized phenylalanines at the GluA2 binding core, showing the direction for further structural modifications.

Original language	English
Journal	European Journal of Medicinal Chemistry
Volume	138
Pages (from-to)	874-883
Number of pages	10
ISSN	0223-5234
DOIs	https://doi.org/10.1016/j.ejmech.2017.07.007
Publication status	Published - 2017

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Szymańska, E., Nielsen, B., Johansen, T. N., Cuñado Moral, A. M., Pickering, D. S., Szczepańska, K., Mickowska, A., & Kieć-Kononowicz, K. (2017). Pharmacological characterization and binding modes of novel racemic and optically active phenylalanine-based antagonists of AMPA receptors. European Journal of Medicinal Chemistry, 138, 874-883. https://doi.org/10.1016/j.ejmech.2017.07.007

Pharmacological characterization and binding modes of novel racemic and optically active phenylalanine-based antagonists of AMPA receptors. / Szymańska, Ewa; Nielsen, Birgitte ; Johansen, Tommy Nørskov et al.
In: European Journal of Medicinal Chemistry, Vol. 138, 2017, p. 874-883.

Research output: Contribution to journal › Journal article › Research › peer-review

Szymańska, E, Nielsen, B , Johansen, TN, Cuñado Moral, AM, Pickering, DS, Szczepańska, K, Mickowska, A & Kieć-Kononowicz, K 2017, 'Pharmacological characterization and binding modes of novel racemic and optically active phenylalanine-based antagonists of AMPA receptors', European Journal of Medicinal Chemistry, vol. 138, pp. 874-883. https://doi.org/10.1016/j.ejmech.2017.07.007

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title = "Pharmacological characterization and binding modes of novel racemic and optically active phenylalanine-based antagonists of AMPA receptors",

abstract = "In order to map out molecular determinants for the competitive blockade of AMPA receptor subtypes, a series of racemic aryl-substituted phenylalanines was synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors. Most of the compounds showed micromolar affinity and preference for AMPA receptors. Individual stereoisomers of selected compounds were further evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. The most potent compound, (–)-2-amino-3-(6-chloro-2',5'-dihydroxy-5-nitro-[1,1'-biphenyl]-3-yl)propanoic acid, the expected R-isomer showing Ki of 1.71 µM at the GluA2 subtype, was found to competitively antagonize GluA2(Q)i receptors in TEVC electrophysiological experiments (Kb = 2.13 µM). Molecular docking experiments allowed us to compare two alternative antagonist binding modes for the synthesized phenylalanines at the GluA2 binding core, showing the direction for further structural modifications.",

author = "Ewa Szyma{\'n}ska and Birgitte Nielsen and Johansen, {Tommy N{\o}rskov} and {Cu{\~n}ado Moral}, {Anna Maria} and Pickering, {Darryl S} and Katarzyna Szczepa{\'n}ska and Anna Mickowska and Katarzyna Kie{\'c}-Kononowicz",

year = "2017",

doi = "10.1016/j.ejmech.2017.07.007",

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journal = "European Journal of Medicinal Chemistry",

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T1 - Pharmacological characterization and binding modes of novel racemic and optically active phenylalanine-based antagonists of AMPA receptors

AU - Szymańska, Ewa

AU - Nielsen, Birgitte

AU - Johansen, Tommy Nørskov

AU - Cuñado Moral, Anna Maria

AU - Pickering, Darryl S

AU - Szczepańska, Katarzyna

AU - Mickowska, Anna

AU - Kieć-Kononowicz, Katarzyna

PY - 2017

Y1 - 2017

N2 - In order to map out molecular determinants for the competitive blockade of AMPA receptor subtypes, a series of racemic aryl-substituted phenylalanines was synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors. Most of the compounds showed micromolar affinity and preference for AMPA receptors. Individual stereoisomers of selected compounds were further evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. The most potent compound, (–)-2-amino-3-(6-chloro-2',5'-dihydroxy-5-nitro-[1,1'-biphenyl]-3-yl)propanoic acid, the expected R-isomer showing Ki of 1.71 µM at the GluA2 subtype, was found to competitively antagonize GluA2(Q)i receptors in TEVC electrophysiological experiments (Kb = 2.13 µM). Molecular docking experiments allowed us to compare two alternative antagonist binding modes for the synthesized phenylalanines at the GluA2 binding core, showing the direction for further structural modifications.

AB - In order to map out molecular determinants for the competitive blockade of AMPA receptor subtypes, a series of racemic aryl-substituted phenylalanines was synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors. Most of the compounds showed micromolar affinity and preference for AMPA receptors. Individual stereoisomers of selected compounds were further evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. The most potent compound, (–)-2-amino-3-(6-chloro-2',5'-dihydroxy-5-nitro-[1,1'-biphenyl]-3-yl)propanoic acid, the expected R-isomer showing Ki of 1.71 µM at the GluA2 subtype, was found to competitively antagonize GluA2(Q)i receptors in TEVC electrophysiological experiments (Kb = 2.13 µM). Molecular docking experiments allowed us to compare two alternative antagonist binding modes for the synthesized phenylalanines at the GluA2 binding core, showing the direction for further structural modifications.

U2 - 10.1016/j.ejmech.2017.07.007

DO - 10.1016/j.ejmech.2017.07.007

M3 - Journal article

C2 - 28738307

SN - 0223-5234

VL - 138

SP - 874

EP - 883

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

Pharmacological characterization and binding modes of novel racemic and optically active phenylalanine-based antagonists of AMPA receptors

Abstract

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