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 Citationer (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.

Originalsprog	Dansk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	56
Udgave nummer	16
Sider (fra-til)	6536−6540
Antal sider	5
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm4006466
Status	Udgivet - 22 aug. 2013

Adgang til dokumentet

10.1021/jm4006466

http://pubs.acs.org/doi/abs/10.1021/jm4006466?prevSearch=krall%2Bjacob&searchHistoryKey=

Citationsformater

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.
I: Journal of Medicinal Chemistry, Bind 56, Nr. 16, 22.08.2013, s. 6536−6540.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 56, nr. 16, s. 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.",

author = "Jacob Krall and Jensen, {Claus Hatt} and S{\o}rensen, {Troels Ersted} and Birgitte Nielsen and Jensen, {Anders A.} and Tommy Sander and Thomas Balle and Bente Fr{\o}lund",

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AU - Krall, Jacob

AU - Jensen, Claus Hatt

AU - Sørensen, Troels Ersted

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AU - Jensen, Anders A.

AU - Sander, Tommy

AU - Balle, Thomas

AU - Frølund, Bente

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AB - 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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