The potency of a series of eight compounds structurally related with 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a potent GABA _A partial agonist exhibiting GABA_C ρ₁ antagonist effect (K_i=25 μM), was determined electrophysiologically using homomeric human GABA_C ρ₁ receptors expressed in Xenopus oocytes. Protolytic properties (pK_a values for the acidic bioisosteric groups) and the presence of steric bulk in the molecules appear to be structural parameters of importance for blockade of the GABA_C ρ₁ receptor. Within this series of moderately potent GABA_C antagonists, only 4,5,6,7- tetrahydropyrazolo[5,4-c]pyridin-3-ol (Aza-THIP) does not interact detectably with GABA_A receptors, and Aza-THIP has the potential of being a useful tool for molecular and behavioural pharmacological studies.