Ro5-4864

Ro5-4864[1] (4'-chlorodiazepam) is a drug which is a benzodiazepine derivative of diazepam.[2] However unlike most benzodiazepine derivatives, Ro5-4864 lacks affinity for GABAA receptors and lacks typical benzodiazepine effects,[3] instead being sedative yet also convulsant and anxiogenic in effects.[4][5][6][7] Ro5-4864 was found to be a potent ligand for the "peripheral benzodiazepine receptor",[8] later renamed to mitochondrial translocator protein 18kDa (TSPO). Despite its convulsant effects, at lower doses Ro5-4864 has proved to be neuroprotective and has become widely used for research into the role of the TSPO protein in neurotoxicity.[9][10][11][12][13][14] In vitro studies and rodent models also suggest the possibility of analgesic,[15] antidepressant,[16] cardioprotective,[17] and anti-cancer effects.[18][19][20][21]

Ro5-4864
Legal status
Legal status
Identifiers
  • 7-Chloro-5-(4-chlorophenyl)-1-methyl-3H-1,4-benzodiazepin-2-one
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard100.162.290
Chemical and physical data
FormulaC16H12Cl2N2O
Molar mass319.185 g·mol−1
3D model (JSmol)
  • Clc3ccc(cc3)C(=NCC1=O)c2cc(Cl)ccc2N1C
  • InChI=1S/C16H12Cl2N2O/c1-20-14-7-6-12(18)8-13(14)16(19-9-15(20)21)10-2-4-11(17)5-3-10/h2-8H,9H2,1H3 ☒N
  • Key:PUMYFTJOWAJIKF-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

See also

References
  1. US 3136815, Reeder E, Sternbach LH, "Amino substituted benzophenone oximes and derivatives thereof", issued 9 June 1964, assigned to F Hoffmann La Roche AG
  2. Manchester KR, Maskell PD, Waters L (March 2018). "Experimental versus theoretical log D7.4 , pKa and plasma protein binding values for benzodiazepines appearing as new psychoactive substances". Drug Testing and Analysis. 10 (8): 1258–1269. doi:10.1002/dta.2387. PMID 29582576. S2CID 31098917.
  3. Patel J, Marangos PJ (May 1982). "Differential effects of GABA on peripheral and central type benzodiazepine binding sites in brain". Neuroscience Letters. 30 (2): 157–160. doi:10.1016/0304-3940(82)90289-0. PMID 6287365. S2CID 19728357.
  4. Weissman BA, Cott J, Hommer D, Quirion R, Paul S, Skolnick P (1983). "Pharmacological, electrophysiological, and neurochemical actions of the convulsant benzodiazepine Ro 5-4864 (4'-chlordiazepam)". Advances in Biochemical Psychopharmacology. 38: 139–151. PMID 6670623.
  5. File SE, Lister RG (January 1983). "The anxiogenic action of Ro 5-4864 is reversed by phenytoin". Neuroscience Letters. 35 (1): 93–96. doi:10.1016/0304-3940(83)90532-3. PMID 6682534. S2CID 11977458.
  6. File SE, Green AR, Nutt DJ, Vincent ND (1984). "On the convulsant action of Ro 5-4864 and the existence of a micromolar benzodiazepine binding site in rat brain". Psychopharmacology. 82 (3): 199–202. doi:10.1007/BF00427773. PMID 6326177. S2CID 28892522.
  7. Pellow S, File SE (July 1984). "Behavioural actions of Ro 5-4864: a peripheral-type benzodiazepine?". Life Sciences. 35 (3): 229–240. doi:10.1016/0024-3205(84)90106-1. PMID 6087055.
  8. Marangos PJ, Patel J, Boulenger JP, Clark-Rosenberg R (July 1982). "Characterization of peripheral-type benzodiazepine binding sites in brain using [3H]Ro 5-4864". Molecular Pharmacology. 22 (1): 26–32. PMID 6289073.
  9. Veiga S, Azcoitia I, Garcia-Segura LM (April 2005). "Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicity". Journal of Neuroscience Research. 80 (1): 129–137. doi:10.1002/jnr.20430. hdl:10261/72513. PMID 15696538. S2CID 23955844.
  10. Leonelli E, Yague JG, Ballabio M, Azcoitia I, Magnaghi V, Schumacher M, et al. (November 2005). "Ro5-4864, a synthetic ligand of peripheral benzodiazepine receptor, reduces aging-associated myelin degeneration in the sciatic nerve of male rats". Mechanisms of Ageing and Development. 126 (11): 1159–1163. doi:10.1016/j.mad.2005.06.001. hdl:10261/72157. PMID 16045970. S2CID 45797879.
  11. Azarashvili T, Grachev D, Krestinina O, Evtodienko Y, Yurkov I, Papadopoulos V, Reiser G (July 2007). "The peripheral-type benzodiazepine receptor is involved in control of Ca2+-induced permeability transition pore opening in rat brain mitochondria". Cell Calcium. 42 (1): 27–39. doi:10.1016/j.ceca.2006.11.004. PMID 17174393.
  12. Mills C, Makwana M, Wallace A, Benn S, Schmidt H, Tegeder I, et al. (February 2008). "Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats". The European Journal of Neuroscience. 27 (4): 937–946. doi:10.1111/j.1460-9568.2008.06065.x. PMID 18333964. S2CID 40302403.
  13. Soustiel JF, Zaaroor M, Vlodavsky E, Veenman L, Weizman A, Gavish M (December 2008). "Neuroprotective effect of Ro5-4864 following brain injury". Experimental Neurology. 214 (2): 201–208. doi:10.1016/j.expneurol.2008.08.008. PMID 18789929. S2CID 2252586.
  14. Giatti S, Pesaresi M, Cavaletti G, Bianchi R, Carozzi V, Lombardi R, et al. (December 2009). "Neuroprotective effects of a ligand of translocator protein-18 kDa (Ro5-4864) in experimental diabetic neuropathy". Neuroscience. 164 (2): 520–529. doi:10.1016/j.neuroscience.2009.08.005. hdl:10261/72515. PMID 19665520. S2CID 11551493.
  15. DalBó S, Nardi GM, Ferrara P, Ribeiro-do-Valle RM, Farges RC (April 2004). "Antinociceptive effects of peripheral benzodiazepine receptors". Pharmacology. 70 (4): 188–194. doi:10.1159/000075547. PMID 15001819. S2CID 1116731.
  16. Gavioli EC, Duarte FS, Bressan E, Ferrara P, Farges RC, De Lima TC (June 2003). "Antidepressant-like effect of Ro5-4864, a peripheral-type benzodiazepine receptor ligand, in forced swimming test". European Journal of Pharmacology. 471 (1): 21–26. doi:10.1016/S0014-2999(03)01789-8. PMID 12809948.
  17. Solhjoo S, O'Rourke B (January 2015). "Mitochondrial instability during regional ischemia-reperfusion underlies arrhythmias in monolayers of cardiomyocytes". Journal of Molecular and Cellular Cardiology. 78: 90–99. doi:10.1016/j.yjmcc.2014.09.024. PMC 4268014. PMID 25268650.
  18. Obame FN, Zini R, Souktani R, Berdeaux A, Morin D (October 2007). "Peripheral benzodiazepine receptor-induced myocardial protection is mediated by inhibition of mitochondrial membrane permeabilization". The Journal of Pharmacology and Experimental Therapeutics. 323 (1): 336–345. doi:10.1124/jpet.107.124255. PMID 17640950. S2CID 12215031.
  19. Veenman L, Papadopoulos V, Gavish M (2007). "Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response". Current Pharmaceutical Design. 13 (23): 2385–2405. doi:10.2174/138161207781368710. PMID 17692008.
  20. Papadopoulos V, Lecanu L (September 2009). "Translocator protein (18 kDa) TSPO: an emerging therapeutic target in neurotrauma". Experimental Neurology. 219 (1): 53–57. doi:10.1016/j.expneurol.2009.04.016. PMC 2728790. PMID 19409385.
  21. Xiao J, Liang D, Zhang H, Liu Y, Li F, Chen YH (April 2010). "4'-Chlorodiazepam, a translocator protein (18 kDa) antagonist, improves cardiac functional recovery during postischemia reperfusion in rats". Experimental Biology and Medicine. 235 (4): 478–486. doi:10.1258/ebm.2009.009291. PMID 20407080. S2CID 6403616.
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