TY - JOUR
T1 - Aza-THIP and related analogues of THIP as GABAC antagonists
AU - Krehan, Dorte
AU - Frølund, Bente
AU - Ebert, Bjarke
AU - Nielsen, Birgitte
AU - Krogsgaard-Larsen, Povl
AU - Johnston, Graham A.R.
AU - Chebib, Mary
PY - 2003/11/17
Y1 - 2003/11/17
N2 - 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 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.
AB - 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 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.
UR - http://www.scopus.com/inward/record.url?scp=0242361214&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2003.09.016
DO - 10.1016/j.bmc.2003.09.016
M3 - Journal article
C2 - 14604650
AN - SCOPUS:0242361214
VL - 11
SP - 4891
EP - 4896
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
SN - 0968-0896
IS - 23
ER -