Aza-THIP and related analogues of THIP as GABAC antagonists

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) rho(1) antagonist effect (K-i = 25 muM), was determined electrophysiologically using homomeric human GABA(C) rho(1) 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) rho(1) 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 delectably with GABA(A) receptors, and Aza-THIP has the potential of being a useful tool for molecular and behavioural pharmacological studies. (C) 2003 Elsevier Ltd. All rights reserved.