Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as ¿-aminobutyric acidA receptor agonists

Jette Gellert Petersen; Rikke Bergmann; Henriette A. Møller; Charlotte Grube Jørgensen; Birgitte Nielsen; Jan Kehler; Karla  Frydenvang; Jesper Kristensen; Thomas Balle; Anders A. Jensen; Uffe Kristiansen; Bente Frølund

doi:10.1021/jm301473k

Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as ¿-aminobutyric acid_A receptor agonists

Jette Gellert Petersen, Rikke Bergmann, Henriette A. Møller, Charlotte Grube Jørgensen, Birgitte Nielsen, Jan Kehler, Karla Frydenvang, Jesper Kristensen, Thomas Balle, Anders A. Jensen, Uffe Kristiansen, Bente Frølund

Department of Chemistry

17 Citations (Scopus)

Abstract

A series of bioisosteric 4-(aminomethyl)-1-hydroxypyrazole (4-AHP) analogues of muscimol, a GABA_A receptor agonist, has been synthesized and pharmacologically characterized at native and selected recombinant GABA_A receptors. The unsubstituted 4-AHP analogue (2a) (EC ₅₀ 19 μM, R_max 69%) was a moderately potent agonist at human α₁β₂γ₂ GABA_A receptors, and in SAR studies substitutions in the 3- and/or 5-position were found to be detrimental to binding affinities. Ligand-receptor docking in an α₁β₂γ₂ GABA_A receptor homology model along with the obtained SAR indicate that 2a and muscimol share a common binding mode, which deviates from the binding mode of the structurally related antagonist series based on 4-(piperidin-4-yl)-1- hydroxypyrazole (4-PHP, 1). Selectivity for α₁β ₂γ₂ over ρ₁ GABA_A receptors was observed for the 5-chloro, 5-bromo, and 5-methyl substituted analogues of 2a illustrating that even small differences in structure can give rise to subtype selectivity.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	3
Pages (from-to)	993-1006
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm301473k
Publication status	Published - 14 Feb 2013

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10.1021/jm301473k

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Petersen, J. G., Bergmann, R., Møller, H. A., Jørgensen, C. G., Nielsen, B., Kehler, J., Frydenvang, K., Kristensen, J., Balle, T., Jensen, A. A., Kristiansen, U., & Frølund, B. (2013). Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as ¿-aminobutyric acid_A receptor agonists. Journal of Medicinal Chemistry, 56(3), 993-1006. https://doi.org/10.1021/jm301473k

Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as ¿-aminobutyric acid_A receptor agonists. / Petersen, Jette Gellert; Bergmann, Rikke; Møller, Henriette A. et al.

In: Journal of Medicinal Chemistry, Vol. 56, No. 3, 14.02.2013, p. 993-1006.

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

Petersen, JG, Bergmann, R, Møller, HA, Jørgensen, CG, Nielsen, B, Kehler, J, Frydenvang, K , Kristensen, J, Balle, T, Jensen, AA , Kristiansen, U & Frølund, B 2013, 'Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as ¿-aminobutyric acid_A receptor agonists', Journal of Medicinal Chemistry, vol. 56, no. 3, pp. 993-1006. https://doi.org/10.1021/jm301473k

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title = "Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as ¿-aminobutyric acidA receptor agonists",

abstract = "A series of bioisosteric 4-(aminomethyl)-1-hydroxypyrazole (4-AHP) analogues of muscimol, a GABAA receptor agonist, has been synthesized and pharmacologically characterized at native and selected recombinant GABAA receptors. The unsubstituted 4-AHP analogue (2a) (EC 50 19 μM, Rmax 69%) was a moderately potent agonist at human α1β2γ2 GABAA receptors, and in SAR studies substitutions in the 3- and/or 5-position were found to be detrimental to binding affinities. Ligand-receptor docking in an α1β2γ2 GABAA receptor homology model along with the obtained SAR indicate that 2a and muscimol share a common binding mode, which deviates from the binding mode of the structurally related antagonist series based on 4-(piperidin-4-yl)-1- hydroxypyrazole (4-PHP, 1). Selectivity for α1β 2γ2 over ρ1 GABAA receptors was observed for the 5-chloro, 5-bromo, and 5-methyl substituted analogues of 2a illustrating that even small differences in structure can give rise to subtype selectivity.",

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AU - Bergmann, Rikke

AU - Møller, Henriette A.

AU - Jørgensen, Charlotte Grube

AU - Nielsen, Birgitte

AU - Kehler, Jan

AU - Frydenvang, Karla

AU - Kristensen, Jesper

AU - Balle, Thomas

AU - Jensen, Anders A.

AU - Kristiansen, Uffe

AU - Frølund, Bente

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AB - A series of bioisosteric 4-(aminomethyl)-1-hydroxypyrazole (4-AHP) analogues of muscimol, a GABAA receptor agonist, has been synthesized and pharmacologically characterized at native and selected recombinant GABAA receptors. The unsubstituted 4-AHP analogue (2a) (EC 50 19 μM, Rmax 69%) was a moderately potent agonist at human α1β2γ2 GABAA receptors, and in SAR studies substitutions in the 3- and/or 5-position were found to be detrimental to binding affinities. Ligand-receptor docking in an α1β2γ2 GABAA receptor homology model along with the obtained SAR indicate that 2a and muscimol share a common binding mode, which deviates from the binding mode of the structurally related antagonist series based on 4-(piperidin-4-yl)-1- hydroxypyrazole (4-PHP, 1). Selectivity for α1β 2γ2 over ρ1 GABAA receptors was observed for the 5-chloro, 5-bromo, and 5-methyl substituted analogues of 2a illustrating that even small differences in structure can give rise to subtype selectivity.

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ER -

Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as ¿-aminobutyric acidA receptor agonists

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Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as ¿-aminobutyric acid_A receptor agonists