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Abstract The correct application of bio(iso)steric replacement , a potent tool for the design of optimized compounds, requires the continuous development of new isosters able to respond to specific target requirements. Among carboxylic acid isosters, as the hydroxylated pentatomic heterocyclic systems, the hydroxy-1,2,3-triazole represents one of the most versatile but less investigated. With the purpose to enlarge its bioisosteric application, we report the results of a study devoted to obtain potential biomimetics of the γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system (CNS). A series of N 1 - and N 2 - functionalized 4-hydroxy-1,2,3-triazole analogues of the previous reported GABA A R ligands, including muscimol, 4-PIOL, and 4-PHP has been synthesized and characterized pharmacologically. Furthermore, this study led to development of straightforward chemical strategies directed to decorate the hydroxytriazole core scaffold, opening for further elaborative studies based on this system. The unsubstituted N 1 - and N 2 -piperidin-4-yl-4-hydroxy-1,2,3-triazole analogues (3a , 4a) of 4-PIOL and 4-PHP showed weak affinity (high to medium micromolar range), whereas substituting the 5-position of the triazole core with a 2-naphthylmethyl or 3,3-diphenylpropyl led to binding affinities in the low micromolar range. Based on electrostatic analysis and docking studies using a α 1 β 2 γ 2 GABA A R homology model we were able to rationalize the observed divergence in SAR for the series of N 1 - and N 2 - piperidin-4-yl-4-hydroxy-1,2,3-triazole analogues, offering more detailed insight into the orthosteric GABA A R binding site. Graphical abstract Image 1 Highlights • Hydroxy-1,2,3-triazole is a poorly investigated bioisostere of the carboxylic acid. • New GABA A R ligands were designed and synthetized using hydroxytriazole scaffolds. • Eight compounds were assayed for GABA A R binding affinity. • Modelling was used to speculate the interaction with the GABA A R binding site. [ABSTRACT FROM AUTHOR]