1421357-22-3Relevant academic research and scientific papers
Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as γ-aminobutyric acidA receptor agonists
Petersen, Jette G.,Bergmann, Rikke,M?ller, Henriette A.,J?rgensen, Charlotte G.,Nielsen, Birgitte,Kehler, Jan,Frydenvang, Karla,Kristensen, Jesper,Balle, Thomas,Jensen, Anders A.,Kristiansen, Uffe,Fr?lund, Bente
, p. 993 - 1006 (2013/03/28)
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.
