Inhibition of gamma-aminobutyric acid uptake by bicuculline analogues.
Enantiomers of norbicuculline, (+)[1S,9R] and (-)[1R,9S]erythro-1-[1'-(4',5'-methylenedioxyphthalidyl)]-6,7-meth ylenedioxy-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 microM [14C]gamma-aminobutyric acid into native plasma membrane vesicles from the rat cerebral cortex at 30 degrees C. The values for the dissociation constants of the reversible inhibition, relative to (+)[1S,9R]bicuculline, in order of increasing inhibition, were: (-)[1R,9S]bicuculline, 3.3; (+)[1S,9R]-bicuculline, 1.0; (-)[1R,9S]norbicuculline, 0.4 approximately (+)[1S,9R]norbicuculline; guvacine, 0.02. The norbicucullines have higher potencies than (+)[1S,9R]bicuculline for the gamma-aminobutyric acid transporter, in contrast to the relative potencies of these inhibitors for the inhibition of function and gamma-aminobutyric acid binding of the gamma-aminobutyric acid type A receptor.
Kardos
J
J
Group of Neurochemistry, Central Research Institute for Chemistry, Hungarian Academy of Sciences, Budapest. jkardos@cric.chemres.hu
Kovács
I
I
Blandl
T
T
Cash
D J
DJ
Simon-Trompler
E
E
Luyen
N D
ND
Dörnyei
G
G
Simonyi
M
M
Blaskó
G
G
Szántay
C
C
D000818:Animals; D001640:Bicuculline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D018756:GABA Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D051381:Rats; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018756:GABA Antagonists; D005680:gamma-Aminobutyric Acid; D001640:Bicuculline