R015-4513

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Ro15-4513 is a weak partial inverse agonist of the benzodiazepine class of drugs, developed by Hoffmann–La Roche in 1984, and is structurally related to the benzodiazepine antidote flumazenil.

The main interest in Ro15-4513 was as an antidote to alcohol. Whereas flumazenil effectively blocks the effects of benzodiazepine agonists such as Xanax and Valium and so is used for treating overdoses of these drugs, Ro15-4513 is less effective at blocking the effects of benzodiazepines but instead has been shown to bind selectively to the same GABA receptor subtypes as ethanol. This meant that in contrast to flumazenil, which is ineffective at treating alcohol overdoses, Ro15-4513 showed potential as a useful antidote.

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, as if only one dose was 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 of its GABA antagonist effects, Ro15-4513 causes serious side effects including both anxiety, and at higher doses, convulsions, which would require careful control of dosing and would cause complications in clinical use. Another problem is that alchol's effects are not purely mediated by GABA receptors, at higher doses alcohol binds to multiple 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 fatal overdoses.

Also, Roche was concerned about the legal implications of introducing an alcohol antidote, as Ro15-4513 blocks the effects of ethanol, but does not remove it from the bloodstream, which could lead to potential problems as the effects of the alcohol would only be masked temporarily, so patients might for instance feel that they are sober and discharge themselves from hospital once the drug took effect, then become drunk again once it wore off, possibly crashing their car or having other accidents which might lead to legal consequences for Roche.

However the discovery of Ro15-4513 has been important in elucidating the mechanism of action of ethanol as used as a recreational drug, and this compound could now be used as a template to design a more effective and longer lasting antidote for ethanol, or alternatively to develop a selective agonist drug which could replicate the beneficial effects of alcohol but with less side effects.

Ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-1,4-benzodiazepine-3-carboxylate

CAS number 91917-65-6

[edit] References

Pharmacology of benzodiazepine receptors: an update by W. Sieghart in Journal of Psychiatry & Neuroscience (1994) Volume 19, pages 24-29.
"Ethanol potentiation of GABAergic transmission in cultured spinal cord neurons involves gamma-aminobutyric acidA-gated chloride channels" by A. K. Mehta and M. K. Ticku in The Journal of Pharmacology and Experimental Therapeutics (1988) Volume 246, pages 558-564. PMID 2457076
"The benzodiazepine receptor inverse agonist Ro15-4513 exacerbates, but does not precipitate, ethanol withdrawal in mice.", Becker HC, Anton RF.,Pharmacol Biochem Behav. 1989 Jan;32(1):163-7. PMID 2543989
Brit. J. of Pharmacology
Wallner M, Hanchar HJ, Olsen RW. Low-dose alcohol actions on alpha4beta3delta GABA-A receptors are reversed by the behavioral alcohol antagonist Ro15-4513. Proc Natl Acad Sci U S A. 2006 May 30;103(22):8540-5.
Hanchar HJ, Chutsrinopkun P, Meera P, Supavilai P, Sieghart W, Wallner M, Olsen RW. Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to alpha4/6beta3delta GABA-A receptors. Proc Natl Acad Sci U S A. 2006 May 30;103(22):8546-51.