Aza-THIP and related analogues of THIP as GABAC antagonists Original Research Article

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 GABAA partial agonist exhibiting GABAC ρ1 antagonist effect (Ki=25 μM), was determined electrophysiologically using homomeric human GABAC ρ1 receptors expressed in Xenopus oocytes. Protolytic properties (pKa 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 GABAC ρ1 receptor. Within this series of moderately potent GABAC antagonists, only 4,5,6,7-tetrahydropyrazolo[5,4-c]pyridin-3-ol (Aza-THIP) does not interact detectably with GABAA receptors, and Aza-THIP has the potential of being a useful tool for molecular and behavioural pharmacological studies.