title: Aza-THIP and related analogues of THIP as GABA C antagonists.
abstract: 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.
authors: Centre for Drug Design and Transport, Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, DK 2100 Copenhagen, Denmark.
authors: Dorte
authors: D
authors: Krehan
authors: Bente
authors: B
authors: Frølund
authors: Bjarke
authors: B
authors: Ebert
authors: Birgitte
authors: B
authors: Nielsen
authors: Povl
authors: P
authors: Krogsgaard-Larsen
authors: Graham A R
authors: GA
authors: Johnston
authors: Mary
authors: M
authors: Chebib
mesh_terms: 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
chemical_list: D001372:Aza Compounds; D018756:GABA Antagonists; C087200:GABA-C receptor; D007555:Isoxazoles; D018079:Receptors, GABA; D011994:Recombinant Proteins; C015542:gaboxadol