Exploring the orthosteric binding site of the γ-aminobutyric acid type A receptor using 4-(piperidin-4-yl)-1-hydroxypyrazoles 3- or 5-imidazolyl substituted: design, synthesis, and pharmacological evaluation

Jacob Krall; Claus Hatt Jensen; Troels Ersted Sørensen; Birgitte Nielsen; Anders A. Jensen; Tommy Sander; Thomas Balle; Bente Frølund

doi:10.1021/jm4006466

Exploring the orthosteric binding site of the γ-aminobutyric acid type A receptor using 4-(piperidin-4-yl)-1-hydroxypyrazoles 3- or 5-imidazolyl substituted: design, synthesis, and pharmacological evaluation

Jacob Krall, Claus Hatt Jensen, Troels Ersted Sørensen, Birgitte Nielsen, Anders A. Jensen, Tommy Sander, Thomas Balle, Bente Frølund

4 Citations (Scopus)

Abstract

A series of 4-(piperidin-4-yl)-1-hydroxypyrazole (4-PHP) 3- or 5-imidazolyl substituted analogues have been designed, synthesized, and characterized pharmacologically. All analogues showed binding affinities in the low micro- to low nanomolar range at native rat GABA_A receptors and were found to be antagonists at the human α₁β₂γ _2s receptor. The structure-activity relationship of the compound series demonstrates distinct differences in size and architecture of previously discovered cavities in the vicinity of the 4-PHP scaffold in the orthosteric binding site.

Original language	Danish
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	16
Pages (from-to)	6536−6540
Number of pages	5
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm4006466
Publication status	Published - 22 Aug 2013

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Cite this

Krall, J., Jensen, C. H., Sørensen, T. E., Nielsen, B., Jensen, A. A., Sander, T., Balle, T., & Frølund, B. (2013). Exploring the orthosteric binding site of the γ-aminobutyric acid type A receptor using 4-(piperidin-4-yl)-1-hydroxypyrazoles 3- or 5-imidazolyl substituted: design, synthesis, and pharmacological evaluation. Journal of Medicinal Chemistry, 56(16), 6536−6540. https://doi.org/10.1021/jm4006466

Exploring the orthosteric binding site of the γ-aminobutyric acid type A receptor using 4-(piperidin-4-yl)-1-hydroxypyrazoles 3- or 5-imidazolyl substituted : design, synthesis, and pharmacological evaluation. / Krall, Jacob; Jensen, Claus Hatt; Sørensen, Troels Ersted et al.

In: Journal of Medicinal Chemistry, Vol. 56, No. 16, 22.08.2013, p. 6536−6540.

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

Krall, J, Jensen, CH, Sørensen, TE, Nielsen, B , Jensen, AA, Sander, T, Balle, T & Frølund, B 2013, 'Exploring the orthosteric binding site of the γ-aminobutyric acid type A receptor using 4-(piperidin-4-yl)-1-hydroxypyrazoles 3- or 5-imidazolyl substituted: design, synthesis, and pharmacological evaluation', Journal of Medicinal Chemistry, vol. 56, no. 16, pp. 6536−6540. https://doi.org/10.1021/jm4006466

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abstract = "A series of 4-(piperidin-4-yl)-1-hydroxypyrazole (4-PHP) 3- or 5-imidazolyl substituted analogues have been designed, synthesized, and characterized pharmacologically. All analogues showed binding affinities in the low micro- to low nanomolar range at native rat GABAA receptors and were found to be antagonists at the human α1β2γ 2s receptor. The structure-activity relationship of the compound series demonstrates distinct differences in size and architecture of previously discovered cavities in the vicinity of the 4-PHP scaffold in the orthosteric binding site.",

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