| Revision as of 13:02, 6 December 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 457348528 of page Ro15-4513 for the Chem/Drugbox validation project (updated: 'CAS_number'). |
Latest revision as of 00:38, 17 October 2024 edit Slothwizard (talk | contribs)Extended confirmed users1,361 edits IUPAC name is in drugbox already, it should not be in ledeTags: Visual edit Mobile edit Mobile web edit |
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{{short description|Chemical compound}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}} |
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{{Infobox drug |
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{{Drugbox |
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| Verifiedfields = changed |
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| verifiedrevid = 417961432 |
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| Watchedfields = changed |
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| IUPAC_name = Ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-1,4-benzodiazepine-3-carboxylate |
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| class = ] ] |
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| verifiedrevid = 464382993 |
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| IUPAC_name = Ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4''H''-imidazo-1,4-benzodiazepine-3-carboxylate |
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| image = Ro15-4513.svg |
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| image = Ro15-4513.svg |
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| width = 250 |
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| width = 255 |
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| image2 = Ro15-45133d.png |
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| image2 = Ro15-45133d.png |
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| width2 = 150 |
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<!--Clinical data--> |
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<!--Clinical data-->| tradename = |
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| pregnancy_category = |
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| legal_status = |
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| routes_of_administration = <!--Pharmacokinetic data--> |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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<!--Pharmacokinetic data--> |
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| elimination_half-life = |
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| bioavailability = |
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| excretion = <!--Identifiers--> |
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| protein_bound = |
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| metabolism = |
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| IUPHAR_ligand = 4296 |
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| CAS_number_Ref = {{cascite|changed|??}} |
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| elimination_half-life = |
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| CAS_number = 91917-65-6 |
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| excretion = |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = S5XGL82O5Y |
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<!--Identifiers--> |
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| ATC_prefix = None |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| ATC_suffix = |
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| CAS_number = <!-- blanked - oldvalue: 91917-65-6 --> |
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| ATC_suffix = |
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| ATC_supplemental = |
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| PubChem = 5081 |
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| PubChem = 5081 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 4903 |
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| ChemSpiderID = 4903 |
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| ChEMBL = 6597 |
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| ChEMBL = 6597 |
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<!--Chemical data--> |
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<!--Chemical data-->| C = 15 |
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| C=15 | H=14 | N=6 | O=3 |
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| H = 14 |
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| N = 6 |
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| molecular_weight = 326.31 g/mol |
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| O = 3 |
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| smiles = ==N/c2cc1C(=O)N(C)Cc3c(ncn3c1cc2)C(=O)OCC |
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| smiles = O=C(OCC)C1=C2CN(C)C(C3=CC(N==)=CC=C3N2C=N1)=O |
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| InChI = 1/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 |
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| InChIKey = CFSOJZTUTOQNIA-UHFFFAOYAJ |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 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 |
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| StdInChI = 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 |
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| StdInChIKey = CFSOJZTUTOQNIA-UHFFFAOYSA-N |
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| StdInChIKey = CFSOJZTUTOQNIA-UHFFFAOYSA-N |
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'''Ro15-4513''' is a weak partial ] of the ] class of drugs, developed by ] in the 1980s.<ref>{{ cite patent | country = US | number = 4868176 | status =patent | title = Novel imidazobenzodiazepines | gdate = 1989-09-19 | inventor = Gardner CR, Hedgecook JR | assign1 = Roussel Uclaf }}</ref> It acts as an inverse agonist (which acts in a similar way as a ]), and can therefore be an ] to the acute impairment caused by ], including ], ], ], ], ], ], and ]. |
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Ro15-4513 is structurally related to the benzodiazepine antidote ]. |
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==Uses== |
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===Original development as alcohol antidote=== |
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The main interest in Ro15-4513 was as an antidote to ] (ethanol). Flumazenil effectively blocks the effects of benzodiazepine agonists such as ] and ], and so is used for treating ] 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 was able to effectively block the effects of ethanol. This meant that in contrast to flumazenil, which is ineffective at treating alcohol ], Ro15-4513 showed potential as a useful alcohol antidote. It is thought that Ro15-4513 antagonizes the effects of ethanol because the ] group at the 8- position of the benzene ring blocks the binding site for ethanol on the α5β3δ subtype of the ]; flumazenil, which has a fluorine at this position, does not block this binding site and so does not counteract the effects of ethanol.{{cn|date=October 2024}} |
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Unfortunately Ro15-4513 had several disadvantages that made it unsuitable for development and marketing. Its fairly short ] 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 ] with short-acting antagonists such as ]). Also, because it antagonizes GABA receptors, Ro15-4513 causes serious side effects including both ] and, at higher doses, ], 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.{{cn|date=October 2024}} |
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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.{{cn|date=October 2024}} |
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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.{{cn|date=October 2024}} |
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===Current use in PET Imaging=== |
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Labelling Ro15-4513 with ] leads to the possibility of its use in ] 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 ] 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 ], ], and ], as it does not selectively label the ] subtype.<ref name="pmid8148363">{{cite journal | author = Sieghart W | title = Pharmacology of benzodiazepine receptors: an update | journal = J Psychiatry Neurosci | volume = 19 | issue = 1 | pages = 24–9 | year = 1994 | pmid = 8148363 | pmc = 1188559 }}</ref><ref name="pmid2457076">{{cite journal | vauthors = Mehta AK, Ticku MK | title = Ethanol potentiation of GABAergic transmission in cultured spinal cord neurons involves gamma-aminobutyric acidA-gated chloride channels | journal = J. Pharmacol. Exp. Ther. | volume = 246 | issue = 2 | pages = 558–64 | year = 1988 | pmid = 2457076 | url = http://jpet.aspetjournals.org/cgi/content/abstract/246/2/558 | access-date = 2008-04-09 | archive-date = 2008-05-08 | archive-url = https://web.archive.org/web/20080508182707/http://jpet.aspetjournals.org/cgi/content/abstract/246/2/558 | url-status = live }}</ref><ref name="pmid2543989">{{cite journal |vauthors=Becker HC, Anton RF | title = The benzodiazepine receptor inverse agonist RO15-4513 exacerbates, but does not precipitate, ethanol withdrawal in mice | journal = Pharmacol. Biochem. Behav. | volume = 32 | issue = 1 | pages = 163–7 | year = 1989 | pmid = 2543989 | doi = 10.1016/0091-3057(89)90227-X | s2cid = 6396416 }}</ref><ref name="pmid16698930">{{cite journal |vauthors=Wallner M, Hanchar HJ, Olsen RW | title = Low-dose alcohol actions on α4β3δ GABAA receptors are reversed by the behavioral alcohol antagonist Ro15-4513 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 22 | pages = 8540–5 | year = 2006 | pmid = 16698930 | doi = 10.1073/pnas.0600194103| pmc = 1482527 | bibcode = 2006PNAS..103.8540W | doi-access = free }}</ref><ref name="pmid16581914">{{cite journal |vauthors=Hanchar HJ, Chutsrinopkun P, Meera P, Supavilai P, Sieghart W, Wallner M, Olsen RW | title = Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to α4/6β3δ GABAA receptors | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 22 | pages = 8546–51 | year = 2006 | pmid = 16581914 | doi = 10.1073/pnas.0509903103| pmc = 1482528 | bibcode = 2006PNAS..103.8546H | doi-access = free }}</ref> |
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==See also== |
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==References== |
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{{Reflist|2}} |
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{{Benzodiazepines}} |
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{{GABAergics}} |
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{{Convulsants}} |
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] |
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