INHIBITION OF GAMMA-AMINOBUTYRIC-ACID UPTAKE BY BICUCULLINE ANALOGS

Enantiomers of norbicuculline, (+)[1S,9R] and -6,7-methylenedioxy-1,2, 3,4-tetrahydroisoquinoline and of the N-methyl derivatives {(+)[1S,9R] and (-)[1R,9S]bicuculline) were found to inhibit the progress of the gamma-aminobutyric acid transporter-mediated uptake of 40 mu M [C-14]g amma-aminobutyric acid into native plasma membrane vesicles from the r at cerebral cortex at 30 degrees C. The values for the dissociation co nstants of the reversible inhibition, relative to (+)[1S,9R]bicucullin e, in order of increasing inhibition, were: (-)[1R,9S]bicuculline, 3.3 ; (+)[1S,9R]-bicuculline, 1.0; (-)[1R,9S]norbicuculline, 0.4 approxima te to (+)[1S,9R]norbicuculline; guvacine, 0.02. The norbicucullines ha ve higher potencies than (+)[1S,9R]bicuculline for the gamma-aminobuty ric acid transporter, in contrast to the relative potencies of these i nhibitors for the inhibition of function and gamma-aminobutyric acid b inding of the gamma-aminobutyric acid type A receptor. (C) 1997 Elsevi er Science B.V.