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

18 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 α₁β ₂γ₂ 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 - 22 Apr 2010

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 et al.

In: Journal of Medicinal Chemistry, Vol. 53, No. 8, 22.04.2010, 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

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abstract = "A series of substituted 1-hydroxypyrazole analogues of the GABAA receptor partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL) have been synthesized and pharmacologically characterized. Several of the analogues displayed Ki in the low nanomolar range at the native GABA A receptors and potent antagonism of the α1β 2γ2 receptor. It appears that several regions situated in proximity to the core of the orthosteric binding site of the GABAA receptor are able to accommodate large hydrophobic substituents.",

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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",

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