Triazolam, an Anomalous Benzodiazepine Receptor Ligand: In Vitro Characterization of Alprazolam and Triazolam Binding

ABSTRACT

Abstract: Both alprazolam and triazolam displaced clonazepam (but not Ro 5–4864) from rat brain membranes with high affinity, showing them to act at central but not peripheral benzodiazepine receptors. At 0°C, 10 μMγ-aminobutyric acid (GABA) increased the ability of alprazolam, but not of triazolam, to displace ethyl-β-carboline-3-carboxylate (β-CCE) and Ro 15–1788 from these receptors. At 37°C, GABA increased the affinity of the receptors for both drugs, with a +GABA/–GABA ratio of 1.5 for each in promoting Ro 15–1788 binding displacement. As both triazolam and alprazolam act as anxiolytics in vivo, the results at 37°C would be compatible with the hypothesis that GABA causes an increase in affinity of drugs that act in this way, but the results at 0°C would not be compatible. At 37°C, alprazolam had a higher IC₅₀ for the benzodiazepine receptor than at 0°C, whereas triazolam showed the reverse effect. The relative IC₅₀ values in vitro at 37°C correlated better with the potency in vivo than those obtained at 0°C. At 0°C, both drugs showed Hill plots with slopes of 0.9–1 with β-CCE and Ro 15–1788. At 37°C, the slopes with triazolam were much reduced, indicating that the drug may have a selective action on a subclass of central benzodiazepine receptors. In the studies reported here, alprazolam behaved like other benzodiazepines, whereas triazolam showed several anomalous properties. It would be of interest if these properties could be related either to the drug's use as a hypnotic or to the side effects it sometimes induces.