piperidines and imidazoleacetic-acid

GABAA receptor agonists modulate [3H]diazepam binding in rat cortical membranes with different efficacies. At 23 degrees C, the relative potencies for enhancement of [3H]diazepam binding by agonists parallel their potencies in inhibiting [3H]gamma-aminobutyric acid [( 3H]GABA) binding. The agonist concentrations needed for enhancement of [3H]diazepam binding are up to 35 times higher than for [3H]GABA binding and correspond closely to the concentrations required for displacement of [3H]bicuculline methochloride (BMC) binding. The maximum enhancement of [3H]diazepam varied among agonists: muscimol = GABA greater than isoguvacine greater than 3-aminopropane sulphonic acid (3APS) = imidazoleacetic acid (IAA) greater than 4,5,6,7-tetrahydroisoxazolo (4,5,6)-pyridin-3-ol (THIP) = taurine greater than piperidine 4-sulphonic acid (P4S). At 37 degrees C, the potencies of agonists remained unchanged, but isoguvacine, 3 APS, and THIP acquired efficacies similar to GABA, whereas IAA, taurine, and P4S maintained their partial agonist profiles. At both temperatures the agonist-induced enhancement of [3H]diazepam binding was reversible by bicuculline methobromide and by the steroid GABA antagonist RU 5135. These results stress the importance of studying receptor-receptor interaction under near-physiological conditions and offer an in vitro assay that may predict the agonist status of putative GABA receptor ligands.

Topics: Androstanes; Animals; Azasteroids; Bicuculline; Cell Membrane; Cerebral Cortex; Diazepam; GABA Antagonists; gamma-Aminobutyric Acid; Imidazoles; Isonicotinic Acids; Isoxazoles; Muscimol; Piperidines; Rats; Receptors, GABA-A; Taurine

The effects of GABA agonists on [3H] flunitrazepam binding were examined in membranes from CNS areas proposed to contain different populations of benzodiazepine binding site subtypes (BZ1/BZ2). Since these effects were broadly similar in both cerebellar and hippocampal membranes, it seems unlikely that GABA receptors interacting with the proposed BZ1/BZ2 binding sites have markedly different properties. Sodium chloride clearly facilitated the potentiating effect of muscimol on [3H] flunitrazepam binding but produced a complex interaction with the effects of GABA itself and the partial agonist imidazoleacetic acid in the phosphate buffer system used.

Topics: Animals; Cerebellum; Flunitrazepam; gamma-Aminobutyric Acid; Hippocampus; Imidazoles; Male; Membranes; Muscimol; Piperidines; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, GABA-A