Ro15-4513

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Ro15-4513
Identifiers
  • Ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-1,4-benzodiazepine-3-carboxylate
JSmol)
  • O=C(OCC)C1=C2CN(C)C(C3=CC(N=[N+]=[N-])=CC=C3N2C=N1)=O
  • InChI=1S/C15H14N6O3/c1-3-24-15(23)13-12-7-20(2)14(22)10-6-9(18-19-16)4-5-11(10)21(12)8-17-13/h4-6,8H,3,7H2,1-2H3 checkY
  • Key:CFSOJZTUTOQNIA-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Ro15-4513 (

3-methyl-3-pentanol, methylpentynol and ethchlorvynol
.

Ro15-4513 is structurally related to the benzodiazepine antidote flumazenil.

Uses

Original development as alcohol antidote

The main interest in Ro15-4513 was as an antidote to

azido group at the 8- position of the benzene ring blocks the binding site for ethanol on the α5β3δ 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

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.

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 be masked only temporarily. As a result, 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 that 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 that could replicate the desired effects of alcohol, but with fewer side effects.

Current use in PET Imaging

Labelling Ro15-4513 with

GABRA1 subtype.[3][4][5][6][7]

See also

References

  1. ^ PubChem. "Ethyl 8-azido-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate". National Center for Biotechnology Information (pubchem.ncbi.nlm.nih.gov). Archived from the original on 2021-05-31. Retrieved 2021-05-31.
  2. ^ US patent 4868176, Gardner CR, Hedgecook JR, "Novel imidazobenzodiazepines", issued 1989-09-19, assigned to Roussel Uclaf 
  3. PMID 8148363
    .
  4. PMID 2457076. Archived
    from the original on 2008-05-08. Retrieved 2008-04-09.
  5. S2CID 6396416
    .
  6. PMID 16698930
    .
  7. PMID 16581914
    .
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