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 GABA_A 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	CA: Schedule IV DE: NpSG (Industrial and scientific use only) UK: Under Psychoactive Substances Act US: Not FDA approved
Identifiers
IUPAC name 7-Chloro-5-(4-chlorophenyl)-1-methyl-3H-1,4-benzodiazepin-2-one
CAS Number	14439-61-3^Y
PubChem CID	1688
ChemSpider	1625^N
UNII	2QW0IK1742
CompTox Dashboard (EPA)	DTXSID3041116
ECHA InfoCard	100.162.290
Chemical and physical data
Formula	C16H12Cl2N2O
Molar mass	319.185 g·mol^−1
3D model (JSmol)	Interactive image
SMILES Clc3ccc(cc3)C(=NCC1=O)c2cc(Cl)ccc2N1C
InChI 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
^NY (what is this?)  (verify)

See also

• Diclazepam (2'-chlorodiazepam)
• PK-11195

References

1. US 3136815
2. Manchester, Kieran R.; Maskell, Peter D.; Waters, Laura (2018). "Experimental versus theoretical log D_7.4, pK_a 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. ISSN 1942-7611. PMID 29582576.
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): 157–60. doi:10.1016/0304-3940(82)90289-0. PMID 6287365.
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: 139–51. PMID 6670623.
5. File SE, Lister RG (January 1983). "The anxiogenic action of Ro 5-4864 is reversed by phenytoin". Neuroscience Letters. 35 (1): 93–6. doi:10.1016/0304-3940(83)90532-3. PMID 6682534.
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.
7. Pellow S, File SE (July 1984). "Behavioural actions of Ro 5-4864: a peripheral-type benzodiazepine?". Life Sciences. 35 (3): 229–40. 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): 129–37. doi:10.1002/jnr.20430. hdl:10261/72513. PMID 15696538.
10. Leonelli E, Yague JG, Ballabio M, Azcoitia I, Magnaghi V, Schumacher M, Garcia-Segura LM, Melcangi RC (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): 1159–63. doi:10.1016/j.mad.2005.06.001. hdl:10261/72157. PMID 16045970.
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, Costigan M, Brown RH, Raivich G, Woolf CJ (February 2008). "Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats". The European Journal of Neuroscience. 27 (4): 937–46. doi:10.1111/j.1460-9568.2008.06065.x. PMID 18333964.
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): 201–8. doi:10.1016/j.expneurol.2008.08.008. PMID 18789929.
14. Giatti S, Pesaresi M, Cavaletti G, Bianchi R, Carozzi V, Lombardi R, Maschi O, Lauria G, Garcia-Segura LM, Caruso D, Melcangi RC (December 2009). "Neuroprotective effects of a ligand of translocator protein-18 kDa (Ro5-4864) in experimental diabetic neuropathy". Neuroscience. 164 (2): 520–9. doi:10.1016/j.neuroscience.2009.08.005. hdl:10261/72515. PMID 19665520.
15. DalBó S, Nardi GM, Ferrara P, Ribeiro-do-Valle RM, Farges RC (April 2004). "Antinociceptive effects of peripheral benzodiazepine receptors". Pharmacology. 70 (4): 188–94. doi:10.1159/000075547. PMID 15001819.
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): 21–6. 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: 90–9. 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): 336–45. doi:10.1124/jpet.107.124255. PMID 17640950.
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): 2385–405. 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): 53–7. 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 (Maywood, N.J.). 235 (4): 478–86. doi:10.1258/ebm.2009.009291. PMID 20407080.