Selective kainate receptor (GluK1) ligands structurally based upon1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization

Raminta Venskutonyte; Stefania Butini; Salvatore Sanna Coccone; Sandra Gemma; Margherita Brindisi; Vinod Kumar; Ergeria Guarino; Samuele Maramai; Salvatore Valenti; Ahmad Amir; Elena Anton Valades; Karla Andrea Frydenvang; Jette Sandholm Jensen Kastrup; Ettore Novellino; Giuseppe Campiani; Darryl S Pickering

doi:10.1021/jm2004078

Selective kainate receptor (GluK1) ligands structurally based upon1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization

Raminta Venskutonyte, Stefania Butini, Salvatore Sanna Coccone, Sandra Gemma, Margherita Brindisi, Vinod Kumar, Ergeria Guarino, Samuele Maramai, Salvatore Valenti, Ahmad Amir, Elena Anton Valades, Karla Andrea Frydenvang, Jette Sandholm Jensen Kastrup, Ettore Novellino, Giuseppe Campiani, Darryl S Pickering

15 Citations (Scopus)

Abstract

The physiological function of kainate receptors (GluK1-GluK5) in the central nervous system is not fully understood yet. With the aim of developing potent and selective GluK1 ligands, we have synthesized a series of new thiophene-based GluK1 agonists (6a-c) and antagonists (7a-d). Pharmacological evaluation revealed that they are selective for the GluK1 subunit, with 7b being the most subtype-selective ligand reported to date (GluK1 vs GluK3). The antagonist 7a was cocrystallized with the GluK1 ligand binding domain, and an X-ray crystallographic analysis revealed the largest flexibility in GluK1 ligand binding domain opening upon binding of a ligand seen to date. The results provide new insights into the molecular mechanism of GluK1 receptor ligand binding and pave the way to the development of new tool compounds for studying kainate receptor function.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	54
Issue number	13
Pages (from-to)	4793-4805
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm2004078
Publication status	Published - 14 Jul 2011

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Venskutonyte, R., Butini, S., Coccone, S. S., Gemma, S., Brindisi, M., Kumar, V., Guarino, E., Maramai, S., Valenti, S., Amir, A., Valades, E. A., Frydenvang, K. A., Kastrup, J. S. J., Novellino, E., Campiani, G., & Pickering, D. S. (2011). Selective kainate receptor (GluK1) ligands structurally based upon1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization. Journal of Medicinal Chemistry, 54(13), 4793-4805. https://doi.org/10.1021/jm2004078

Selective kainate receptor (GluK1) ligands structurally based upon1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization. / Venskutonyte, Raminta; Butini, Stefania; Coccone, Salvatore Sanna et al.
In: Journal of Medicinal Chemistry, Vol. 54, No. 13, 14.07.2011, p. 4793-4805.

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

Venskutonyte, R, Butini, S, Coccone, SS, Gemma, S, Brindisi, M, Kumar, V, Guarino, E, Maramai, S, Valenti, S, Amir, A, Valades, EA, Frydenvang, KA , Kastrup, JSJ, Novellino, E, Campiani, G & Pickering, DS 2011, 'Selective kainate receptor (GluK1) ligands structurally based upon1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization', Journal of Medicinal Chemistry, vol. 54, no. 13, pp. 4793-4805. https://doi.org/10.1021/jm2004078

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title = "Selective kainate receptor (GluK1) ligands structurally based upon1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization",

abstract = "The physiological function of kainate receptors (GluK1-GluK5) in the central nervous system is not fully understood yet. With the aim of developing potent and selective GluK1 ligands, we have synthesized a series of new thiophene-based GluK1 agonists (6a-c) and antagonists (7a-d). Pharmacological evaluation revealed that they are selective for the GluK1 subunit, with 7b being the most subtype-selective ligand reported to date (GluK1 vs GluK3). The antagonist 7a was cocrystallized with the GluK1 ligand binding domain, and an X-ray crystallographic analysis revealed the largest flexibility in GluK1 ligand binding domain opening upon binding of a ligand seen to date. The results provide new insights into the molecular mechanism of GluK1 receptor ligand binding and pave the way to the development of new tool compounds for studying kainate receptor function.",

author = "Raminta Venskutonyte and Stefania Butini and Coccone, {Salvatore Sanna} and Sandra Gemma and Margherita Brindisi and Vinod Kumar and Ergeria Guarino and Samuele Maramai and Salvatore Valenti and Ahmad Amir and Valades, {Elena Anton} and Frydenvang, {Karla Andrea} and Kastrup, {Jette Sandholm Jensen} and Ettore Novellino and Giuseppe Campiani and Pickering, {Darryl S}",

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doi = "10.1021/jm2004078",

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T1 - Selective kainate receptor (GluK1) ligands structurally based upon1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization

AU - Venskutonyte, Raminta

AU - Butini, Stefania

AU - Coccone, Salvatore Sanna

AU - Gemma, Sandra

AU - Brindisi, Margherita

AU - Kumar, Vinod

AU - Guarino, Ergeria

AU - Maramai, Samuele

AU - Valenti, Salvatore

AU - Amir, Ahmad

AU - Valades, Elena Anton

AU - Frydenvang, Karla Andrea

AU - Kastrup, Jette Sandholm Jensen

AU - Novellino, Ettore

AU - Campiani, Giuseppe

AU - Pickering, Darryl S

PY - 2011/7/14

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N2 - The physiological function of kainate receptors (GluK1-GluK5) in the central nervous system is not fully understood yet. With the aim of developing potent and selective GluK1 ligands, we have synthesized a series of new thiophene-based GluK1 agonists (6a-c) and antagonists (7a-d). Pharmacological evaluation revealed that they are selective for the GluK1 subunit, with 7b being the most subtype-selective ligand reported to date (GluK1 vs GluK3). The antagonist 7a was cocrystallized with the GluK1 ligand binding domain, and an X-ray crystallographic analysis revealed the largest flexibility in GluK1 ligand binding domain opening upon binding of a ligand seen to date. The results provide new insights into the molecular mechanism of GluK1 receptor ligand binding and pave the way to the development of new tool compounds for studying kainate receptor function.

AB - The physiological function of kainate receptors (GluK1-GluK5) in the central nervous system is not fully understood yet. With the aim of developing potent and selective GluK1 ligands, we have synthesized a series of new thiophene-based GluK1 agonists (6a-c) and antagonists (7a-d). Pharmacological evaluation revealed that they are selective for the GluK1 subunit, with 7b being the most subtype-selective ligand reported to date (GluK1 vs GluK3). The antagonist 7a was cocrystallized with the GluK1 ligand binding domain, and an X-ray crystallographic analysis revealed the largest flexibility in GluK1 ligand binding domain opening upon binding of a ligand seen to date. The results provide new insights into the molecular mechanism of GluK1 receptor ligand binding and pave the way to the development of new tool compounds for studying kainate receptor function.

U2 - 10.1021/jm2004078

DO - 10.1021/jm2004078

M3 - Journal article

C2 - 21619066

SN - 0022-2623

VL - 54

SP - 4793

EP - 4805

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 13

ER -

Selective kainate receptor (GluK1) ligands structurally based upon1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization

Abstract

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