Analogues of 3-Hydroxyisoxazole-Containing Glutamate Receptor Ligands Based on the 3-Hydroxypyrazole-Moiety: Design, Synthesis and Pharmacological Characterization

Lars Jørgensen; Birgitte Nielsen; Darryl S Pickering; Anders Skov Kristensen; Karla Andrea Frydenvang; Ulf Madsen; Rasmus Prætorius Clausen

doi:10.1007/s11064-014-1332-0

Analogues of 3-Hydroxyisoxazole-Containing Glutamate Receptor Ligands Based on the 3-Hydroxypyrazole-Moiety: Design, Synthesis and Pharmacological Characterization

Lars Jørgensen, Birgitte Nielsen, Darryl S Pickering, Anders Skov Kristensen, Karla Andrea Frydenvang, Ulf Madsen, Rasmus Prætorius Clausen

LUKKET: Institut for Lægemiddeldesign og Farmakologi

3 Citationer (Scopus)

Abstract

A series of analogues of the glutamate receptor ligands (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) and AMOA were synthesized in which the 3-hydroxyisoxazole moiety was exchanged for a 3-hydroxypyrazole moiety. This exchange enables further substitution at the additional nitrogen atom in the heterocyclic core. Several of the analogues have activity at AMPA receptors equipotent to the antagonist ATPO, demonstrating that additional substitution can be accommodated in the antagonist binding site. Modelling studies offer an explanation for the pharmacological pattern observed for the compounds and suggest that this scaffold may be developed further to obtain subtype selective antagonists.

Originalsprog	Engelsk
Tidsskrift	Neurochemical Research
Vol/bind	39
Udgave nummer	10
Sider (fra-til)	1895-1905
Antal sider	11
ISSN	0364-3190
DOI	https://doi.org/10.1007/s11064-014-1332-0
Status	Udgivet - 24 sep. 2014

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10.1007/s11064-014-1332-0

Citationsformater

Jørgensen, L., Nielsen, B., Pickering, D. S., Kristensen, A. S., Frydenvang, K. A., Madsen, U., & Clausen, R. P. (2014). Analogues of 3-Hydroxyisoxazole-Containing Glutamate Receptor Ligands Based on the 3-Hydroxypyrazole-Moiety: Design, Synthesis and Pharmacological Characterization. Neurochemical Research, 39(10), 1895-1905. https://doi.org/10.1007/s11064-014-1332-0

Analogues of 3-Hydroxyisoxazole-Containing Glutamate Receptor Ligands Based on the 3-Hydroxypyrazole-Moiety: Design, Synthesis and Pharmacological Characterization. / Jørgensen, Lars; Nielsen, Birgitte ; Pickering, Darryl S et al.

I: Neurochemical Research, Bind 39, Nr. 10, 24.09.2014, s. 1895-1905.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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AU - Pickering, Darryl S

AU - Kristensen, Anders Skov

AU - Frydenvang, Karla Andrea

AU - Madsen, Ulf

AU - Clausen, Rasmus Prætorius

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AB - A series of analogues of the glutamate receptor ligands (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) and AMOA were synthesized in which the 3-hydroxyisoxazole moiety was exchanged for a 3-hydroxypyrazole moiety. This exchange enables further substitution at the additional nitrogen atom in the heterocyclic core. Several of the analogues have activity at AMPA receptors equipotent to the antagonist ATPO, demonstrating that additional substitution can be accommodated in the antagonist binding site. Modelling studies offer an explanation for the pharmacological pattern observed for the compounds and suggest that this scaffold may be developed further to obtain subtype selective antagonists.

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Analogues of 3-Hydroxyisoxazole-Containing Glutamate Receptor Ligands Based on the 3-Hydroxypyrazole-Moiety: Design, Synthesis and Pharmacological Characterization

Abstract

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