Inhibition of γ-aminobutyric acid uptake by bicuculline analogues

Enantiomers of norbicuculline, (+)[1 S,9 R] and (−)[1 R,9 S] erythro-1-[1′-(4′,5′-methylenedioxyphthalidyl)]-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline and of the N-methyl derivatives {(+)[1 S,9 R] and (−)[1 R,9 S]bicuculline} were found to inhibit the progress of the γ-aminobutyric acid transporter-mediated uptake of 40 μM [ 14 C ] γ-aminobutyric acid into native plasma membrane vesicles from the rat cerebral cortex at 30°C. The values for the dissociation constants of the reversible inhibition, relative to (+)[1 S,9 R]bicuculline, in order of increasing inhibition, were: (−)[1 R,9 S]bicuculline, 3.3; (+)[1 S,9 R]-bicuculline, 1.0; (−)[1 R,9 S] norbicuculline, 0.4≈(+)[1 S,9 R] norbicuculline; guvacine, 0.02. The norbicucullines have higher potencies than (+)[1 S,9 R]bicuculline for the γ-aminobutyric acid transporter, in contrast to the relative potencies of these inhibitors for the inhibition of function and γ-aminobutyric acid binding of the γ-aminobutyric acid type A receptor.