Design, synthesis and structure-activity relationships of novel phenylalanine-based amino acids as kainate receptors ligands

Ewa Szymańska; Paulina Chałupnik; Katarzyna Szczepańska; Ana Maria Cuñado Moral; Darryl S Pickering; Birgitte Nielsen; Tommy Nørskov Johansen; Kieć-Kononowicz Kieć-Kononowicz

doi:10.1016/j.bmcl.2016.09.075

Design, synthesis and structure-activity relationships of novel phenylalanine-based amino acids as kainate receptors ligands

Ewa Szymańska, Paulina Chałupnik, Katarzyna Szczepańska, Ana Maria Cuñado Moral, Darryl S Pickering, Birgitte Nielsen, Tommy Nørskov Johansen, Kieć-Kononowicz Kieć-Kononowicz

1 Citation (Scopus)

Abstract

A new series of carboxyaryl-substituted phenylalanines was designed, synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors as well as at cloned homomeric kainate receptors GluK1–GluK3. Among them, six compounds bound to GluK1 receptor subtypes with reasonable affinity (K_ivalues in the range of 4.9–7.5 μM). A structure–activity relationship (SAR) for the obtained series, focused mainly on the pharmacological effect of structural modifications in the 4- and 5-position of the phenylalanine ring, was established. To illustrate the results, molecular docking of the synthesized series to the X-ray structure of GluK1 ligand binding core was performed. The influence of individual substituents at the phenylalanine ring for both the affinity and selectivity at AMPA, GluK1 and GluK3 receptors was analyzed, giving directions for future studies.

Original language	English
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	26
Issue number	22
Pages (from-to)	5568-5572
Number of pages	5
ISSN	0960-894X
DOIs	https://doi.org/10.1016/j.bmcl.2016.09.075
Publication status	Published - 2016

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Szymańska, E., Chałupnik, P., Szczepańska, K., Moral, A. M. C., Pickering, D. S., Nielsen, B., Johansen, T. N., & Kieć-Kononowicz, K.-K. (2016). Design, synthesis and structure-activity relationships of novel phenylalanine-based amino acids as kainate receptors ligands. Bioorganic & Medicinal Chemistry Letters, 26(22), 5568-5572. https://doi.org/10.1016/j.bmcl.2016.09.075

Szymańska, E, Chałupnik, P, Szczepańska, K, Moral, AMC, Pickering, DS , Nielsen, B , Johansen, TN & Kieć-Kononowicz, K-K 2016, 'Design, synthesis and structure-activity relationships of novel phenylalanine-based amino acids as kainate receptors ligands', Bioorganic & Medicinal Chemistry Letters, vol. 26, no. 22, pp. 5568-5572. https://doi.org/10.1016/j.bmcl.2016.09.075

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title = "Design, synthesis and structure-activity relationships of novel phenylalanine-based amino acids as kainate receptors ligands",

abstract = "A new series of carboxyaryl-substituted phenylalanines was designed, synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors as well as at cloned homomeric kainate receptors GluK1–GluK3. Among them, six compounds bound to GluK1 receptor subtypes with reasonable affinity (Kivalues in the range of 4.9–7.5 μM). A structure–activity relationship (SAR) for the obtained series, focused mainly on the pharmacological effect of structural modifications in the 4- and 5-position of the phenylalanine ring, was established. To illustrate the results, molecular docking of the synthesized series to the X-ray structure of GluK1 ligand binding core was performed. The influence of individual substituents at the phenylalanine ring for both the affinity and selectivity at AMPA, GluK1 and GluK3 receptors was analyzed, giving directions for future studies.",

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

year = "2016",

doi = "10.1016/j.bmcl.2016.09.075",

language = "English",

volume = "26",

pages = "5568--5572",

journal = "Bioorganic & Medicinal Chemistry Letters",

issn = "0960-894X",

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TY - JOUR

T1 - Design, synthesis and structure-activity relationships of novel phenylalanine-based amino acids as kainate receptors ligands

AU - Szymańska, Ewa

AU - Chałupnik, Paulina

AU - Szczepańska, Katarzyna

AU - Moral, Ana Maria Cuñado

AU - Pickering, Darryl S

AU - Nielsen, Birgitte

AU - Johansen, Tommy Nørskov

AU - Kieć-Kononowicz, Kieć-Kononowicz

PY - 2016

Y1 - 2016

N2 - A new series of carboxyaryl-substituted phenylalanines was designed, synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors as well as at cloned homomeric kainate receptors GluK1–GluK3. Among them, six compounds bound to GluK1 receptor subtypes with reasonable affinity (Kivalues in the range of 4.9–7.5 μM). A structure–activity relationship (SAR) for the obtained series, focused mainly on the pharmacological effect of structural modifications in the 4- and 5-position of the phenylalanine ring, was established. To illustrate the results, molecular docking of the synthesized series to the X-ray structure of GluK1 ligand binding core was performed. The influence of individual substituents at the phenylalanine ring for both the affinity and selectivity at AMPA, GluK1 and GluK3 receptors was analyzed, giving directions for future studies.

AB - A new series of carboxyaryl-substituted phenylalanines was designed, synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors as well as at cloned homomeric kainate receptors GluK1–GluK3. Among them, six compounds bound to GluK1 receptor subtypes with reasonable affinity (Kivalues in the range of 4.9–7.5 μM). A structure–activity relationship (SAR) for the obtained series, focused mainly on the pharmacological effect of structural modifications in the 4- and 5-position of the phenylalanine ring, was established. To illustrate the results, molecular docking of the synthesized series to the X-ray structure of GluK1 ligand binding core was performed. The influence of individual substituents at the phenylalanine ring for both the affinity and selectivity at AMPA, GluK1 and GluK3 receptors was analyzed, giving directions for future studies.

U2 - 10.1016/j.bmcl.2016.09.075

DO - 10.1016/j.bmcl.2016.09.075

M3 - Journal article

C2 - 27765511

SN - 0960-894X

VL - 26

SP - 5568

EP - 5572

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 22

ER -

Design, synthesis and structure-activity relationships of novel phenylalanine-based amino acids as kainate receptors ligands

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