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Latest revision as of 13:22, 1 October 2024 edit BD2412 (talk | contribs)Autopatrolled, IP block exemptions, Administrators2,447,950 editsm Clean up spacing around commas and other punctuation fixes, replaced: ,A → , A, ,G → , G, ,M → , M, ,Y → , Y, , → , (4)Tag: AWB |
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{{Short description|Chemical compound}} |
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{{Drugbox |
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| verifiedrevid = 444676362 |
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| IUPAC_name = 7-chloro-5-(4-chlorophenyl)-1-methyl-3H-1,4-benzodiazepin-2-one |
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| image = Ro5-4864_structure.png |
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| width = 180 |
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{{Infobox drug |
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<!--Clinical data--> |
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| verifiedrevid = 451564612 |
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| IUPAC_name = ''N''-benzyl-''N''-methyl-1-phenylpyrrolopyrazine-3-carboxamide |
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<!--Pharmacokinetic data--> |
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| image = GML-1 structure.svg |
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| bioavailability = |
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| metabolism = |
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| width = 177 |
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<!--Identifiers--> |
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| PubChem = 122393153 |
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| CAS_number = 14439-61-3 |
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| ChemSpiderID = 67166536 |
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| ATC_prefix = none |
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| PubChem = 1688 |
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<!--Chemical data--> |
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| C=16 | H=12 | Cl=2 | N=2 | O=1 |
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| C=22 | H=19 | N=3 | O=1 |
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| StdInChI=1S/C22H19N3O/c1-24(15-17-9-4-2-5-10-17)22(26)19-16-25-14-8-13-20(25)21(23-19)18-11-6-3-7-12-18/h2-14,16H,15H2,1H3 |
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| molecular_weight = 319.185 |
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| StdInChIKey = QFYYHTVZHIEVCW-UHFFFAOYSA-N |
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| smiles = Clc3ccc(cc3)C(=NCC1=O)c2cc(Cl)ccc2N1C |
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| SMILES = CN(CC1=CC=CC=C1)C(=O)C2=CN3C=CC=C3C(=N2)C4=CC=CC=C4 |
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'''GML-1''' is a ] (peripheral benzodiazepine receptor) ligand with ] activity.<ref name="pmid25937237">{{cite journal |vauthors=Mokrov GV, Deeva OA, Gudasheva TA, Yarkov SA, Yarkova MA, Seredenin SB |title=Design, synthesis and anxiolytic-like activity of 1-arylpyrrolopyrazine-3-carboxamides |journal=Bioorganic & Medicinal Chemistry |volume=23 |issue=13 |pages=3368–78 |date=Jul 2015 |pmid=25937237 |doi= 10.1016/j.bmc.2015.04.049}}</ref> Its binding affinity (Ki value) to TSPO is comparable with ]. GML-1 is selective for TSPO versus the central benzodiazepine receptor (CBR, ]). The compound GML-1 was the most active of a series of 1-arylpyrrolopyrazine-3-carboxamides, and its anxiolytic effects were examined using the ] test (OFT) and the ] (EPM) test. The EPM test is a general anxiety test measuring the time spent by animals in the open or the enclosed arms. When compound was administered to CD-1 mice at the dose of 1.0 mg/kg, it significantly increased the percentage of open arm entries and the time spent in the open arms. GML-1 is a potential antianxiety agent. |
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The TSPO-mechanism of anxiolytic action of GML-1 was proved by inhibitor analysis with TSPO antagonist ] that blocks effect of GML-1.<ref name="pmid25937237"/> |
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The involvement of neurosteroids in the mechanism of action of GML-1 was confirmed by co-administration of GML-1 with neurosteroid synthesis inhibitors. The anxiolytic effect of GML-1 in elevated plus-maze tests was completely blocked by the neurosteroidogenic-enzyme inhibitors ] and ].<ref>{{cite journal |vauthors=Yarkova MA, Mokrov GV, Gudasheva TA, Seredenin SB |title=Novel PyrroloPyrazines (TSPO Ligands) with Anxiolytic Activity Dependent on Neurosteroid Biosynthesis |journal=Pharmaceutical Chemistry Journal |volume=50 |issue=8 |pages=501–4 |date=Nov 2016 |doi= 10.1007/s11094-016-1476-0|s2cid=35338758 }}</ref> |
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'''Ro5-4864''' ('''4'-Chlorodiazepam''') is a drug which is a ] derivative, the 4'-chloro derivative of ]. However unlike most benzodiazepine derivatives, Ro5-4864 lacks affinity for ] ] and lacks typical benzodiazepine effects,<ref name="pmid6287365">{{cite journal |author=Patel J, Marangos PJ |title=Differential effects of GABA on peripheral and central type benzodiazepine binding sites in brain |journal=Neuroscience Letters |volume=30 |issue=2 |pages=157–60 |year=1982 |month=May |pmid=6287365 |doi= |url=}}</ref> instead being ] yet also ] and ] in effects.<ref name="pmid6670623">{{cite journal |author=Weissman BA, Cott J, Hommer D, Quirion R, Paul S, Skolnick P |title=Pharmacological, electrophysiological, and neurochemical actions of the convulsant benzodiazepine Ro 5-4864 (4'-chlordiazepam) |journal=Advances in Biochemical Psychopharmacology |volume=38 |issue= |pages=139–51 |year=1983 |pmid=6670623 |doi= |url=}}</ref><ref name="pmid6682534">{{cite journal |author=File SE, Lister RG |title=The anxiogenic action of Ro 5-4864 is reversed by phenytoin |journal=Neuroscience Letters |volume=35 |issue=1 |pages=93–6 |year=1983 |month=January |pmid=6682534 |doi= |url=}}</ref><ref name="pmid6326177">{{cite journal |author=File SE, Green AR, Nutt DJ, Vincent ND |title=On the convulsant action of Ro 5-4864 and the existence of a micromolar benzodiazepine binding site in rat brain |journal=Psychopharmacology |volume=82 |issue=3 |pages=199–202 |year=1984 |pmid=6326177 |doi= |url=}}</ref><ref name="pmid6087055">{{cite journal |author=Pellow S, File SE |title=Behavioural actions of Ro 5-4864: a peripheral-type benzodiazepine? |journal=Life Sciences |volume=35 |issue=3 |pages=229–40 |year=1984 |month=July |pmid=6087055 |doi= 10.1016/0024-3205(84)90106-1|url=}}</ref> Ro5-4864 was found to be a potent ligand for the "peripheral benzodiazepine receptor",<ref name="pmid6289073">{{cite journal |author=Marangos PJ, Patel J, Boulenger JP, Clark-Rosenberg R |title=Characterization of peripheral-type benzodiazepine binding sites in brain using Ro 5-4864 |journal=Molecular Pharmacology |volume=22 |issue=1 |pages=26–32 |year=1982 |month=July |pmid=6289073 |doi= |url=}}</ref> later renamed to ]. Interestingly despite its convulsant effects, at lower doses Ro5-4864 has proved to be ] and has become widely used for research into the role of the TSPO protein in neurotoxicity,<ref name="pmid15696538">{{cite journal |author=Veiga S, Azcoitia I, Garcia-Segura LM |title=Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicity |journal=Journal of Neuroscience Research |volume=80 |issue=1 |pages=129–37 |year=2005 |month=April |pmid=15696538 |doi=10.1002/jnr.20430 |url=}}</ref><ref name="pmid16045970">{{cite journal |author=Leonelli E, Yague JG, Ballabio M, Azcoitia I, Magnaghi V, Schumacher M, Garcia-Segura LM, Melcangi RC |title=Ro5-4864, a synthetic ligand of peripheral benzodiazepine receptor, reduces aging-associated myelin degeneration in the sciatic nerve of male rats |journal=Mechanisms of Ageing and Development |volume=126 |issue=11 |pages=1159–63 |year=2005 |month=November |pmid=16045970 |doi=10.1016/j.mad.2005.06.001 |url=}}</ref><ref name="pmid17174393">{{cite journal |author=Azarashvili T, Grachev D, Krestinina O, Evtodienko Y, Yurkov I, Papadopoulos V, Reiser G |title=The peripheral-type benzodiazepine receptor is involved in control of Ca2+-induced permeability transition pore opening in rat brain mitochondria |journal=Cell Calcium |volume=42 |issue=1 |pages=27–39 |year=2007 |month=July |pmid=17174393 |doi=10.1016/j.ceca.2006.11.004 |url=}}</ref><ref name="pmid18333964">{{cite journal |author=Mills C, Makwana M, Wallace A, Benn S, Schmidt H, Tegeder I, Costigan M, Brown RH, Raivich G, Woolf CJ |title=Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats |journal=The European Journal of Neuroscience |volume=27 |issue=4 |pages=937–46 |year=2008 |month=February |pmid=18333964 |doi=10.1111/j.1460-9568.2008.06065.x |url=}}</ref><ref name="pmid18789929">{{cite journal |author=Soustiel JF, Zaaroor M, Vlodavsky E, Veenman L, Weizman A, Gavish M |title=Neuroprotective effect of Ro5-4864 following brain injury |journal=Experimental Neurology |volume=214 |issue=2 |pages=201–8 |year=2008 |month=December |pmid=18789929 |doi=10.1016/j.expneurol.2008.08.008 |url=}}</ref><ref name="pmid19665520">{{cite journal |author=Giatti S, Pesaresi M, Cavaletti G, Bianchi R, Carozzi V, Lombardi R, Maschi O, Lauria G, Garcia-Segura LM, Caruso D, Melcangi RC |title=Neuroprotective effects of a ligand of translocator protein-18 kDa (Ro5-4864) in experimental diabetic neuropathy |journal=Neuroscience |volume=164 |issue=2 |pages=520–9 |year=2009 |month=December |pmid=19665520 |doi=10.1016/j.neuroscience.2009.08.005 |url=}}</ref> as well as having ] <ref name="pmid15001819">{{cite journal |author=DalBó S, Nardi GM, Ferrara P, Ribeiro-do-Valle RM, Farges RC |title=Antinociceptive effects of peripheral benzodiazepine receptors |journal=Pharmacology |volume=70 |issue=4 |pages=188–94 |year=2004 |month=April |pmid=15001819 |doi=10.1159/000075547 |url=}}</ref> and possible ],<ref name="pmid12809948">{{cite journal |author=Gavioli EC, Duarte FS, Bressan E, Ferrara P, Farges RC, De Lima TC |title=Antidepressant-like effect of Ro5-4864, a peripheral-type benzodiazepine receptor ligand, in forced swimming test |journal=European Journal of Pharmacology |volume=471 |issue=1 |pages=21–6 |year=2003 |month=June |pmid=12809948 |doi= 10.1016/S0014-2999(03)01789-8|url=}}</ref> cardioprotective and anti-cancer effects.<ref name="pmid17640950">{{cite journal |author=Obame FN, Zini R, Souktani R, Berdeaux A, Morin D |title=Peripheral benzodiazepine receptor-induced myocardial protection is mediated by inhibition of mitochondrial membrane permeabilization |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=323 |issue=1 |pages=336–45 |year=2007 |month=October |pmid=17640950 |doi=10.1124/jpet.107.124255 |url=}}</ref><ref name="pmid17692008">{{cite journal |author=Veenman L, Papadopoulos V, Gavish M |title=Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response |journal=Current Pharmaceutical Design |volume=13 |issue=23 |pages=2385–405 |year=2007 |pmid=17692008 |doi= 10.2174/138161207781368710|url=}}</ref><ref name="pmid19409385">{{cite journal |author=Papadopoulos V, Lecanu L |title=Translocator protein (18 kDa) TSPO: an emerging therapeutic target in neurotrauma |journal=Experimental Neurology |volume=219 |issue=1 |pages=53–7 |year=2009 |month=September |pmid=19409385 |pmc=2728790 |doi=10.1016/j.expneurol.2009.04.016 |url=}}</ref><ref name="pmid20407080">{{cite journal |author=Xiao J, Liang D, Zhang H, Liu Y, Li F, Chen YH |title=4'-Chlorodiazepam, a translocator protein (18 kDa) antagonist, improves cardiac functional recovery during postischemia reperfusion in rats |journal=Experimental Biology and Medicine (Maywood, N.J.) |volume=235 |issue=4 |pages=478–86 |year=2010 |month=April |pmid=20407080 |doi=10.1258/ebm.2009.009291 |url=}}</ref> |
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The tablet dosage form of GML-1 was developed and showed pronounced anxiolytic activity after intragastric administration in rats in a wide range of doses.<ref>{{cite journal |vauthors=Yarkova MA, Blynskaya EV, Yudina DV, Mokrov GV, Gudasheva TA, Alekseev KV |title=Development and Study of Anxiolytic Effect of GML-1 Tablet Dosage Form |journal=Pharmaceutical Chemistry Journal |volume=53 |issue=4 |pages=342–346 |date=Jul 2019 |doi= 10.1007/s11094-019-02003-1|s2cid=195878442 }}</ref> |
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==See also== |
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==References== |
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==References== |
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{{reflist}} |
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{{Reflist}} |
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{{Translocator protein modulators}} |
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{{Benzodiazepines}} |
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{{pharma-stub}} |
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{{Anxiolytic-stub}} |