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 μM at 2°C and 37°C. γ-Aminobutyric acid (GABA) decreased the affinity of tacrine for the receptor, suggesting that tacrine may act as an inverse agonist. A Hill coefficient < 1 was observed under all conditions. Allosteric interactions may explain this behaviour, since 100 μM 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 I 50 = 188 μM. Bicuculline methiodide was 4 times as potent ( I 50 = 49 μM). The interaction of tacrine with GABA or benzodiazepine binding sites is unlikely to be of clinical significance.