Ro15-4513

Uses

Photoaffinity label

Ro 15‑4513, is an azide derivative of Ro 15‑1788 (flumazenil) and was first prepared as a photoaffinity label of benzodiazepine receptors.

Alcohol antidote

It was later discovered that Ro15-4513 was as an antidote to alcohol (ethanol). Flumazenil effectively blocks the effects of benzodiazepine agonists such as alprazolam and diazepam, and so is used for treating overdoses of these drugs, but does not reverse the central nervous system depressant effects of ethanol. Ro15-4513 was somewhat less effective than flumazenil at blocking the effects of benzodiazepines, but was able to effectively block the effects of ethanol. This contrasted with flumazenil, which does not antagonize the central nervous system effects of ethanol, and led to interest in Ro15-4513 as a potential alcohol antidote. It is thought that Ro15-4513 antagonizes the effects of ethanol because the azido group at the 8-position of the benzene ring blocks an ethanol-sensitive binding site on the α5β3δ subtype of the GABA_A receptor. Flumazenil, which has a fluorine substituent at this position, does not block this site and therefore does not counteract the effects of ethanol.

Unfortunately Ro15-4513 had several disadvantages that made it unsuitable for development and marketing. Its fairly short half-life means that several repeated doses would have to be given over an extended period, since if only one dose were used it would wear off before the alcohol had been metabolised and the patient would relapse (similar to the problems with renarcotization seen when treating overdoses of long-acting opioids such as methadone with short-acting antagonists such as naloxone). Also, because it antagonizes GABA receptors, Ro15-4513 causes serious side effects including both anxiety and, at higher doses, seizures, which would require careful control of dosing and would cause complications in clinical use. Another problem is that alcohol's effects are not purely mediated by GABA receptors; at higher doses, alcohol binds to several other targets as well, so while Ro15-4513 is an effective antidote against moderate levels of alcohol intoxication, it might be ineffective at treating life-threatening overdoses.

There were concerns about the legal and clinical implications of introducing an alcohol antidote that blocks the effect of ethanol without accelerating its clearance from the bloodstream. The temporary nature of the antagonistic effect meant that intoxication could re-emerge once the drug wore off, as the underlying alcohol remained present.

The discovery of Ro15-4513 contributed to a clearer understanding of the mechanisms by which ethanol exerts its effects in the central nervous system. Insights gained from studies of this compound have informed subsequent research into the development of ethanol antagonists and other modulators of GABA_A receptor function, including efforts to design agents with longer duration of action or altered side-effect profiles.

Current use in PET Imaging

Labelling Ro15-4513 with carbon-11 leads to the possibility of its use in PET imaging of the brain. The specificity of the compound to a small number of GABA receptor sub-types leads to the generation, with accurate modelling, of detailed images with well-defined limbic and cortical structures. These images can be useful in quantitatively analysing conditions such as addiction, that are known to be, at least in part, associated with the GABAergic system. The images produced are similar to those for labelled flumazenil, though the distribution varies especially in regions such as the occipital lobe, cerebellum, and basal ganglia, as it does not selectively label the GABRA1 subtype.

References

References

1. "Novel imidazobenzodiazepines".
2. (May 2006). "Alcohol-sensitive GABA receptors and alcohol antagonists". Proceedings of the National Academy of Sciences of the United States of America.
3. (June 1984). "Photoaffinity labeling of benzodiazepine receptors with a partial inverse agonist". European Journal of Pharmacology.
4. (2015). "The legacy of the benzodiazepine receptor: from flumazenil to enhancing cognition in Down syndrome and social interaction in autism". Advances in Pharmacology.
5. (2018). "Goodman & Gilman's: The Pharmacological Basis of Therapeutics". McGraw-Hill Education LLC.
6. (November 1988). "Ro 15-4513: partial inverse agonism at the BZR and interaction with ethanol". Pharmacology, Biochemistry, and Behavior.
7. (2005). "Ro15-4513 and ethanol interactions: possible mechanisms". Alcohol.
8. (2001). "Reversal of alcohol intoxication by benzodiazapine receptor ligands". Pharmacology & Therapeutics.
9. (January 1994). "Pharmacology of benzodiazepine receptors: an update". Journal of Psychiatry & Neuroscience.
10. (August 1988). "Ethanol potentiation of GABAergic transmission in cultured spinal cord neurons involves gamma-aminobutyric acidA-gated chloride channels". The Journal of Pharmacology and Experimental Therapeutics.
11. (January 1989). "The benzodiazepine receptor inverse agonist RO15-4513 exacerbates, but does not precipitate, ethanol withdrawal in mice". Pharmacology, Biochemistry, and Behavior.
12. (May 2006). "Low-dose alcohol actions on alpha4beta3delta GABAA receptors are reversed by the behavioral alcohol antagonist Ro15-4513". Proceedings of the National Academy of Sciences of the United States of America.
13. (May 2006). "Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to alpha4/6beta3delta GABAA receptors". Proceedings of the National Academy of Sciences of the United States of America.