Synthesis and Biological Evaluation of 4‑(Aminomethyl)-1-hydroxypyrazole Analogues of Muscimol as γ‑Aminobutyric Acid_A Receptor Agonists

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 (<b>2a</b>) (EC₅₀ 19 μM, <i>R</i>_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 <b>2a</b> 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, <b>1</b>). Selectivity for α₁β₂γ₂ over ρ₁ GABA_A receptors was observed for the 5-chloro, 5-bromo, and 5-methyl substituted analogues of <b>2a</b> illustrating that even small differences in structure can give rise to subtype selectivity