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Systematic (IUPAC) name
benzyl N-(3-{[(2S)-2-amino-4-(methylthio)butyl]dithio}-2-benzylpropanoyl)-L-phenylalaninate
CAS Number 135949-60-9
PubChem CID 119600
Synonyms RB-101; phenylmethyl (2S)-2-[(2-([(2S)-2-amino-4-methylsulfanylbutyl]disulfanylmethyl)-3-phenylpropanoyl)amino]-3-phenylpropanoate
Chemical data
Formula C31H38N2O3S3
Molar mass 582.84 g/mol[[Script error: No such module "String".]]
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RB-101 is a drug that acts as an enkephalinase inhibitor, which is used in scientific research.

RB-101 is a prodrug which acts by splitting at the disulfide bond once inside the brain, to form two selective enzyme inhibitors and blocking both types of the zinc-metallopeptidase enkephalinase enzymes. This inhibits the breakdown of the endogenous opioid peptides known as enkephalins.[1] These two enzymes, aminopeptidase N (APN) and neutral endopeptidase 24.11 (NEP), are responsible for the breakdown of both kinds of enkephalin naturally found in the body, and so RB-101 causes a build up of both Met-enkephalin and Leu-enkephalin.[2][3]

These peptides act primarily at the delta opioid receptor, although they also stimulate the mu opioid receptor to some extent through a delta-opioid receptor mediated interaction with another peptide cholecystokinin, and the enzyme-inhibiting effects of RB-101 thus produce indirect stimulation of both of these opioid receptor subtypes.[4] This causes RB-101 to be strongly synergistic with cholecystokinin antagonists.[5][6]

Unlike the more commonly used enkephalinase inhibitor racecadotril‎, which only acts peripherally and has antidiarrheal effects, RB-101 is able to enter the brain, and thus produces a range of effects, acting as an analgesic, anxiolytic and antidepressant.[7] The antidepressant and anxiolytic actions are thought to be mediated through the delta opioid receptor, while the analgesic effects most likely result from a mix of mu and delta activity.[8] Animal studies suggest that RB-101 is also likely to be useful in relieving the symptoms of acute opioid withdrawal[9] and in the management of opioid dependence.[10][11]

A significant advantage of inhibiting the breakdown of endogenous opioid peptides rather than stimulating opioid receptors with exogenous drugs is that the levels of opioid peptides are only increased slightly from natural levels, thus avoiding overstimulation and downregulation of the opioid receptors. This means that even when RB-101 is used in high doses for extended periods of time, there is no development of dependence on the drug or tolerance to its analgesic effects.[12][13] Consequently even though RB-101 is able to produce potent analgesic effects via the opioid system, it is unlikely to be addictive.[14]

Unlike conventional opioid agonists, RB-101 also failed to produce respiratory depression, which suggests it might be a much safer drug than traditional opioid painkillers.[15] RB-101 also powerfully potentiated the effects of traditional analgesics such as ibuprofen and morphine, suggesting that it could be used to boost the action of a low dose of normal opioids which would otherwise be ineffective.[16]

RB-101 itself is not orally active and so has not been developed for medical use in humans, however modification of the drug has led to newer orally acting compounds such as RB-120 and RB-3007, which may be more likely to be adopted for medical use if clinical trials are successful.[17][18][19][20][21]

See also


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  1. Roques BP. Peptidomimetics as receptors agonists or peptidase inhibitors: a structural approach in the field of enkephalins, ANP and CCK. Biopolymers. 1992 Apr;32(4):407-10. PMID 1320419
  2. Noble F, Soleilhac JM, Soroca-Lucas E, Turcaud S, Fournie-Zaluski MC, Roques BP. Inhibition of the enkephalin-metabolizing enzymes by the first systemically active mixed inhibitor prodrug RB 101 induces potent analgesic responses in mice and rats. Journal of Pharmacology and Experimental Therapeutics. 1992 Apr;261(1):181-90. PMID 1560364
  3. Fournié-Zaluski MC, Coric P, Turcaud S, Lucas E, Noble F, Maldonado R, Roques BP. "Mixed inhibitor-prodrug" as a new approach toward systemically active inhibitors of enkephalin-degrading enzymes. Journal of Medicinal Chemistry. 1992 Jun 26;35(13):2473-81. PMID 1352352
  4. Noble F, Smadja C, Roques BP. Role of endogenous cholecystokinin in the facilitation of mu-mediated antinociception by delta-opioid agonists. Journal of Pharmacology and Experimental Therapeutics. 1994 Dec;271(3):1127-34. PMID 7996417
  5. Valverde O, Maldonado R, Fournie-Zaluski MC, Roques BP. Cholecystokinin B antagonists strongly potentiate antinociception mediated by endogenous enkephalins. Journal of Pharmacology and Experimental Therapeutics. 1994 Jul;270(1):77-88. PMID 8035345
  6. Honore P, Buritova J, Fournié-Zaluski MC, Roques BP, Besson JM. Antinociceptive effects of RB101, a complete inhibitor of enkephalin-catabolizing enzymes, are enhanced by a cholecystokinin type B receptor antagonist, as revealed by noxiously evoked spinal c-Fos expression in rats. Journal of Pharmacology and Experimental Therapeutics. 1997 Apr;281(1):208-17. PMID 9103499
  7. Jutkiewicz EM, Torregrossa MM, Sobczyk-Kojiro K, Mosberg HI, Folk JE, Rice KC, Watson SJ, Woods JH. Behavioral and neurobiological effects of the enkephalinase inhibitor RB101 relative to its antidepressant effects. European Journal of Pharmacology. 2006 Feb 15;531(1-3):151-9. PMID 16442521
  8. Jutkiewicz EM. RB101-mediated protection of endogenous opioids: potential therapeutic utility? CNS Drug Reviews. 2007 Summer;13(2):192-205. PMID 17627672
  9. Maldonado R, Valverde O, Ducos B, Blommaert AG, Fournie-Zaluski MC, Roques BP. Inhibition of morphine withdrawal by the association of RB 101, an inhibitor of enkephalin catabolism, and the CCKB antagonist PD-134,308. British Journal of Pharmacology. 1995 Mar;114(5):1031-9. PMID 7780637
  10. Ruiz F, Fournié-Zaluski MC, Roques BP, Maldonado R. Similar decrease in spontaneous morphine abstinence by methadone and RB 101, an inhibitor of enkephalin catabolism. British Journal of Pharmacology. 1996 Sep;119(1):174-82. PMID 8872371
  11. Roques BP, Noble F. Association of enkephalin catabolism inhibitors and CCK-B antagonists: a potential use in the management of pain and opioid addiction. Neurochemical Research. 1996 Nov;21(11):1397-410. PMID 8947930
  12. Noble F, Turcaud S, Fournié-Zaluski MC, Roques BP. Repeated systemic administration of the mixed inhibitor of enkephalin-degrading enzymes, RB101, does not induce either antinociceptive tolerance or cross-tolerance with morphine. European Journal of Pharmacology. 1992 Nov 13;223(1):83-9. PMID 1478260
  13. Noble F, Coric P, Turcaud S, Fournié-Zaluski MC, Roques BP. Assessment of physical dependence after continuous perfusion into the rat jugular vein of the mixed inhibitor of enkephalin-degrading enzymes, RB 101. European Journal of Pharmacology. 1994 Mar 3;253(3):283-7. PMID 8200422
  14. Noble F, Fournié-Zaluski MC, Roques BP. Unlike morphine the endogenous enkephalins protected by RB101 are unable to establish a conditioned place preference in mice. European Journal of Pharmacology. 1993 Jan 12;230(2):139-49. PMID 8422896
  15. Boudinot E, Morin-Surun M, Foutz AS, Fournié-Zaluski M, Roques BP, Denavit-Saubié M. Effects of the potent analgesic enkephalin-catabolizing enzyme inhibitors RB101 and kelatorphan on respiration. Pain. 2001 Feb 1;90(1-2):7-13. PMID 11166965
  16. Nieto MM, Wilson J, Walker J, Benavides J, Fournié-Zaluski MC, Roques BP, Noble F. Facilitation of enkephalins catabolism inhibitor-induced antinociception by drugs classically used in pain management. Neuropharmacology. 2001 Sep;41(4):496-506. PMID 11543770
  17. Noble F, Smadja C, Valverde O, Maldonado R, Coric P, Turcaud S, Fournié-Zaluski MC, Roques BP. Pain-suppressive effects on various nociceptive stimuli (thermal, chemical, electrical and inflammatory) of the first orally active enkephalin-metabolizing enzyme inhibitor RB 120. Pain. 1997 Dec;73(3):383-91. PMID 9469529
  18. Le Guen S, Mas Nieto M, Canestrelli C, Chen H, Fournié-Zaluski MC, Cupo A, Maldonado R, Roques BP, Noble F. Pain management by a new series of dual inhibitors of enkephalin degrading enzymes: long lasting antinociceptive properties and potentiation by CCK2 antagonist or methadone. Pain. 2003 Jul;104(1-2):139-48. PMID 12855323
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