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Unusual interactions of benzodiazepine receptor antagonists

Abstract

Two compounds have recently been described which act as potent benzodiazepine (BDZ) antagonists in vivo and which, in vitro, show high affinity and selectivity for the BDZ receptor of the mammalian central nervous system (CNS). One, ethyl β-carboline-3-carboxylate (β-CCE), was extracted from human urine and may be related to an endogenous ligand for the BDZ receptor1–3. It reverses the effects of BDZs in vivo4,5 and in vitro6, but also has intrinsic activity, as it lowers the seizure threshold to drugs antagonistic to the action of γ-aminobutyric acid (GABA)5,7. The other compound, an imidazodiazepine (Ro 15-1788), which is also a potent and specific antagonist of BDZ binding in vivo and in vitro8, blocked the sedative, hypnotic and anticonvulsant actions of conventional BDZs, without demonstrating any intrinsic activity9,10. Because of the different profiles of action of these two BDZ ‘antagonists’, we have here investigated their interactions in two well established systems for assessing BDZ activity: seizure thresholds in vivo11 and the action of GABA on cervical sympathetic ganglia in vitro12. We find that Ro 15-1788 not only opposes the actions of BDZs but also is an effective antagonist of β-CCE in both systems. At high doses it has BDZ-like activity, suggesting that it may be a partial agonist at the BDZ receptor site.

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Nutt, D., Cowen, P. & Little, H. Unusual interactions of benzodiazepine receptor antagonists. Nature 295, 436–438 (1982). https://doi.org/10.1038/295436a0

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