Ethyl β-carboline-3-carboxylate shows differential benzodiazepine receptor interaction

Abstract

High-affinity binding of ³H-diazepam and ³H-flunitrazepam has provided evidence for the presence of benzodiazepine receptors on brain neurones^1–6. Pharmacological evidence showing a clear correlation between receptor affinity and in vivo pharmacological potency for several benzodiazepines⁷ and a link between benzodiazepine receptors and GABA (γ-aminobutyric acid) receptors at the molecular level^8,9, indicates that these receptors are relevant to the pharmacological and clinical effects of benzodiazepines. In searching for possible endogeneous ligands for benzodiazepine receptors we have recently isolated ethyl β-carboline-3-carboxylate (β-CCE) from human urine and brain, and shown that β-CCE has a higher affinity than diazepam for brain benzodiazepine receptors¹⁰. β-CCE itself is probably not present in the brain, but may be closely related to an endogenous benzodiazepine receptor ligand¹⁰. We report here that β-CCE, in contrast to benzodiazepines, can distinguish clearly between benzodiazepine receptors in cerebellum and hippocampus. This result strongly indicates that benzodiazepine receptors are not a single class of non-interacting entities. It has not been possible to determine whether two distinct receptors are present and/or whether true negative cooperativity exists among hippocampal, but not cerebellar, benzodiazepine receptors.