Novel 4-(piperidin-4-yl)-1-hydroxypyrazoles as gamma-aminobutyric acidA receptor ligands: synthesis, pharmacology, and structure-activity relationships

Henriette A Møller; Tommy Sander; Jesper Langgaard Kristensen; Birgitte Nielsen; Jacob Krall; Marianne Lerbæk Bergmann; Bolette Christiansen; Thomas Balle; Anders Asbjørn Jensen; Bente Flensborg Frølund

doi:10.1021/jm100106r

Novel 4-(piperidin-4-yl)-1-hydroxypyrazoles as gamma-aminobutyric acid_A receptor ligands: synthesis, pharmacology, and structure-activity relationships

Henriette A Møller, Tommy Sander, Jesper Langgaard Kristensen, Birgitte Nielsen, Jacob Krall, Marianne Lerbæk Bergmann, Bolette Christiansen, Thomas Balle, Anders Asbjørn Jensen, Bente Flensborg Frølund

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

22 Citations (Scopus)

Abstract

A series of substituted 1-hydroxypyrazole analogues of the GABA(A) receptor partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL) have been synthesized and pharmacologically characterized. Several of the analogues displayed K(i) in the low nanomolar range at the native GABA(A) receptors and potent antagonism of the alpha(1)beta(2)gamma(2) receptor. It appears that several regions situated in proximity to the core of the orthosteric binding site of the GABA(A) receptor are able to accommodate large hydrophobic substituents.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	8
Pages (from-to)	3417-3421
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm100106r
Publication status	Published - 2010

Bibliographical note

Keywords: Animals; Cell Line; GABA Antagonists; GABA Plasma Membrane Transport Proteins; Humans; Hydrophobicity; Ligands; Membrane Potentials; Models, Molecular; Piperidines; Pyrazoles; Rats; Receptors, GABA-A; Structure-Activity Relationship; Synaptic Membranes

Keywords

Former Faculty of Pharmaceutical Sciences

Access to Document

10.1021/jm100106r

Cite this

Møller, H. A., Sander, T., Kristensen, J. L., Nielsen, B., Krall, J., Bergmann, M. L., Christiansen, B., Balle, T., Jensen, A. A., & Frølund, B. F. (2010). Novel 4-(piperidin-4-yl)-1-hydroxypyrazoles as gamma-aminobutyric acid_A receptor ligands: synthesis, pharmacology, and structure-activity relationships. Journal of Medicinal Chemistry, 53(8), 3417-3421. https://doi.org/10.1021/jm100106r

Novel 4-(piperidin-4-yl)-1-hydroxypyrazoles as gamma-aminobutyric acid_A receptor ligands : synthesis, pharmacology, and structure-activity relationships. / Møller, Henriette A; Sander, Tommy; Kristensen, Jesper Langgaard ; Nielsen, Birgitte; Krall, Jacob; Bergmann, Marianne Lerbæk; Christiansen, Bolette; Balle, Thomas; Jensen, Anders Asbjørn ; Frølund, Bente Flensborg.

In: Journal of Medicinal Chemistry, Vol. 53, No. 8, 2010, p. 3417-3421.

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

Møller, HA, Sander, T, Kristensen, JL , Nielsen, B, Krall, J, Bergmann, ML, Christiansen, B, Balle, T, Jensen, AA & Frølund, BF 2010, 'Novel 4-(piperidin-4-yl)-1-hydroxypyrazoles as gamma-aminobutyric acid_A receptor ligands: synthesis, pharmacology, and structure-activity relationships', Journal of Medicinal Chemistry, vol. 53, no. 8, pp. 3417-3421. https://doi.org/10.1021/jm100106r

Møller, Henriette A ; Sander, Tommy ; Kristensen, Jesper Langgaard ; Nielsen, Birgitte ; Krall, Jacob ; Bergmann, Marianne Lerbæk ; Christiansen, Bolette ; Balle, Thomas ; Jensen, Anders Asbjørn ; Frølund, Bente Flensborg. / Novel 4-(piperidin-4-yl)-1-hydroxypyrazoles as gamma-aminobutyric acid_A receptor ligands : synthesis, pharmacology, and structure-activity relationships. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 8. pp. 3417-3421.

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abstract = "A series of substituted 1-hydroxypyrazole analogues of the GABA(A) receptor partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL) have been synthesized and pharmacologically characterized. Several of the analogues displayed K(i) in the low nanomolar range at the native GABA(A) receptors and potent antagonism of the alpha(1)beta(2)gamma(2) receptor. It appears that several regions situated in proximity to the core of the orthosteric binding site of the GABA(A) receptor are able to accommodate large hydrophobic substituents.",

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