Aza-THIP and related analogues of THIP as GABA C 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 microM), 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 detectably with GABA(A) receptors, and Aza-THIP has the potential of being a useful tool for molecular and behavioural pharmacological studies.
Krehan
Dorte
D
Centre for Drug Design and Transport, Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, DK 2100 Copenhagen, Denmark.
Frølund
Bente
B
Ebert
Bjarke
B
Nielsen
Birgitte
B
Krogsgaard-Larsen
Povl
P
Johnston
Graham A R
GA
Chebib
Mary
M
D000818:Animals; D001372:Aza Compounds / Q000737:chemistry; D018756:GABA Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D018079:Receptors, GABA / Q000187:drug effects*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D014981:Xenopus
D001372:Aza Compounds; D018756:GABA Antagonists; C087200:GABA-C receptor; D007555:Isoxazoles; D018079:Receptors, GABA; D011994:Recombinant Proteins; C015542:gaboxadol