5-(4-Piperidyl)isoxazol-3-ol (4-PIOL, 10), a structural analog of 4-aminobutanoic acid (GABA, 1) and the GABAa agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 5), is a low-efficacy partial GABAa agonist. A number of compounds bioisosterically derived from 10, including 5-(4-piperidyl)isothiazol-3-ol (11), 3-(4-piperidyl)isoxazol-5-ol (12), 5-(1, 2, 3, 6-tetrahydropyrid-4-yl)isoxazol-3-ol (13), and 5-(1, 2, 3, 6-tetrahydropyrid-4-yl)isothiazol-3-ol (14), were synthesized and tested as GABAa receptor ligands. Whereas none of these compounds significantly affected GABAb receptor binding or GABA uptake, they showed affinities for GABAa receptor sites in the low-micromolar range. Using cultured cerebral cortical neurons and whole-cell patch-clamp techniques, the efficacies of these compounds relative to that of the full GABAa agonist, isoguvacine (8) (20 μM), were determined. The relative efficacy of 11, which has a higher receptor affinity (IC₅₀ = 1.3 ± 0.3 μM) than 10 (IC₅₀ = 9.3 ± 2.6 μM), was comparable with that of 10 (30-35%). The tetrahydropyridine analog of 10, compound 13, showed a markedly lower receptor affinity (IC₅₀ = 32 ± 10 μM) and apparently a lower relative efficacy than 10. The corresponding unsaturated analog of 11, compound 14, showed a slightly weaker receptor affinity (IC50 = 4.0 ± 2.0 μM) but a significantly higher relative efficacy (5055%) than 11. The 5-isoxazolol isomer of 10, compound 12, showed a reduced receptor affinity (IC₅₀ = 26 ± 7 μM) and a very low relative efficacy. Substitution of propanoic or propenoic acid moieties for the acidic heterocyclic units of these compounds gave the monocyclic amino acids 15-18, which have very little or no affinity for GABA_A receptor sites.