Agonist and antagonist benzodiazepine receptor interaction in vitro

Abstract

A representative of a novel series of imidazodiazepines, Ro 15-1788, selectively antagonizes all major central actions of benzodiazepines by competitive, high-affinity interactions with benzodiazepine receptors (BR) in the central nervous system (CNS)^1–3. Doses of Ro 15-1788 sufficient to antagonize benzodiazepine actions have been shown per se to lack phamacological action in animals and man^1–4. Thus Ro 15-1788 provides a highly selective tool for experimental investigations of BR-mediated events and is of therapeutic value in all cases where a rapid termination of benzodiazepine actions is indicated. Using ³H-labelled Ro 15–1788 as radioligand in equilibrium binding studies in vitro, we show here that ³H-Ro 15-1788 interacts with the same number of BR sites as the agonist ³H-clonazepam in various brain regions. However, their mode of receptor interaction is different. In conditions which alter receptor affinity for ³H-clonazepam binding, such as addition of γ-aminobutyric acid (GABA) or certain ions, no change is seen in ³H-Ro 15-1788 binding. This effect can be used to distinguish between benzodiazepine receptor agonists and antagonists in vitro. Furthermore, the thermodynamics of agonist and antagonist receptor interaction are different, but only at temperatures above 21 °C.