Coupling between agonist and chloride ionophore sites of the GABAA receptor: agonist/antagonist efficacy of 4-PIOL

Abstract Eight γ-aminobutyric acid (GABA) mimetics were tested on their ability to differentiate native GABA A receptor subtypes present in various rat brain regions. In rat brain cryostat sections, little regional variations by the agonistic actions of muscimol, thiomuscimol, 4,5,6,7-tetrahydroisoazolo(5,4-c)pyridin-3-ol, piperidine-4-sulphonic acid, taurine and β-alanine on [ 35 S] t -butylbicyclophosphorothionate ([ 35 S]TBPS) binding to GABA A receptor channels were found. They were very similar to those found for GABA itself and indicated no direct correlation with single subunit distributions for any of these compounds. Only the low-efficacy GABA mimetic 5-(4-piperidyl)isoxazol-3-ol (4-PIOL) acted like a weak partial agonist or antagonist depending on the brain area. As the cerebellar granule cell layer was relatively insensitive to both modes of action, we tested 4-PIOL in recombinant α1β2γ2 (widespread major subtype) and α6β2γ2 (cerebellar granule cell restricted) receptors where it had different effects on GABA-modulated [ 35 S]TBPS binding and on electrophysiological responses. 4-PIOL may thus serve as a potential lead for receptor subtype selective compounds.