The interaction of tacrine with benzodiazepine and GABA binding sites of guinea pig brain.
Tacrine (1,2,3,4-tetrahydro-9-acridinamine) inhibited binding of [3H]flunitrazepam to benzodiazepine receptors of guinea pig hippocampus with an inhibition constant of 46 microM at 2 degrees C and 37 degrees C. gamma-Aminobutyric acid (GABA) decreased the affinity of tacrine for the receptor, suggesting that tacrine may act as an inverse agonist. A Hill coefficient less than 1 was observed under all conditions. Allosteric interactions may explain this behaviour, since 100 microM tacrine increased the rate of dissociation of [3H]flunitrazepam from the receptor. Tacrine inhibited the binding of 11 nM [3H]GABA to GABA receptors of guinea pig cerebral cortex with I50 = 188 microM. Bicuculline methiodide was 4 times as potent (I50 = 49 microM). The interaction of tacrine with GABA or benzodiazepine binding sites is unlikely to be of clinical significance.
Dawson
R M
RM
Materials Research Laboratory, Defence Science and Technology Organization, Ascot Vale, Vic. Australia.
Poretski
M
M
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005445:Flunitrazepam / Q000378:metabolism; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000187:drug effects*; D013619:Tacrine / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
D011963:Receptors, GABA-A; D013619:Tacrine; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; D001640:Bicuculline