Nature 295, 436 - 438 (04 February 1982); doi:10.1038/295436a0

Unusual interactions of benzodiazepine receptor antagonists

David J. Nutt^*, Philip J. Cowen^* & Hilary J. Little^†

^*MRC Unit and University Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK
^†Department of Pharmacology, Oxford University, South Parks Road, Oxford 0X1 3QT, UK

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 -carboline-3-carboxylate (-CCE), was extracted from human urine and may be related to an endogenous ligand for the BDZ receptor^1–3. It reverses the effects of BDZs in vivo ^4,5 and in vitro ⁶, but also has intrinsic activity, as it lowers the seizure threshold to drugs antagonistic to the action of -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 vitro ⁸, blocked the sedative, hypnotic and anticonvulsant actions of conventional BDZs, without demonstrating any intrinsic activity^9,10. 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 vivo ¹¹ and the action of GABA on cervical sympathetic ganglia in vitro ¹². We find that Ro 15-1788 not only opposes the actions of BDZs but also is an effective antagonist of -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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