Ro15-4513
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| Formula | C15H14N6O3 |
| Molar mass | 326.31 g/mol |
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Ro15-4513 is a weak partial inverse agonist of the benzodiazepine class of drugs, developed by Hoffmann–La Roche in the 1980s. It acts as a competitive antagonist, and can therefore be an antidote to the acute impairment caused by alcohol.
Ro15-4513 is structurally related to the benzodiazepine antidote flumazenil.
The main interest in Ro15-4513 was as an antidote to alcohol. Flumazenil effectively blocks the effects of benzodiazepine agonists such as alprazolam and diazepam and so is used for treating overdoses of these drugs but is ineffective in blocking alcohol actions. Ro15-4513 was somewhat less effective than flumazenil at blocking the effects of benzodiazepines, but instead selectively blocked the effects of ethanol. This meant that in contrast to flumazenil, which is ineffective at treating alcohol overdoses, Ro15-4513 showed potential as a useful 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 the binding site for ethanol on the α4β3δ subtype of the GABAA receptor; flumazenil, which has a fluorine at this position, does not block this binding site and so 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 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 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.
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