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Drugs used to treat various disorders target GABA Areceptors. To develop α subunit selective compounds, we synthesized 5-(4-piperidyl)-3-isoxazolol (4-PIOL) derivatives. The 3-isoxazolol moiety was substituted by 1,3,5-oxadiazol-2-one, 1,3,5-oxadiazol-2-thione, and substituted 1,2,4-triazol-3-ol heterocycles with modifications to the basic piperidine substituent as well as substituents without basic nitrogen. Compounds were screened by [ 3H]muscimol binding and in patch-clamp experiments with heterologously expressed GABA Aα iβ 3γ 2receptors ( i= 1−6). The effects of 5-aminomethyl-3 H-[1,3,4]oxadiazol-2-one 5dwere comparable to GABA for all α subunit isoforms. 5-piperidin-4-yl-3 H-[1,3,4]oxadiazol-2-one 5aand 5-piperidin-4-yl-3 H-[1,3,4]oxadiazol-2-thione 6awere weak agonists at α 2-, α 3-, and α 5-containing receptors. When coapplied with GABA, they were antagonistic in α 2-, α 4-, and α 6-containing receptors and potentiated α 3-containing receptors. 6aprotected GABA binding site cysteine-substitution mutants α 1F64C and α 1S68C from reacting with methanethiosulfonate-ethylsulfonate. 6aspecifically covalently modified the α 1R66C thiol, in the GABA binding site, through its oxadiazolethione sulfur. These results demonstrate the feasibility of synthesizing α subtype selective GABA mimetic drugs. [ABSTRACT FROM AUTHOR]