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.