RB-101

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RB-101
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Clinical data
Other namesRB-101; phenylmethyl (2S)-2-[(2-([(2S)-2-amino-4-methylsulfanylbutyl]disulfanylmethyl)-3-phenylpropanoyl)amino]-3-phenylpropanoate
Identifiers
  • benzyl N-(3-{[(2S)-2-amino-4-(methylthio)butyl]dithio}-2-benzylpropanoyl)-L-phenylalaninate
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C31H38N2O3S3
Molar mass 582.84 g·mol−1
3D model (JSmol)
  • CSCC[C@@H](CSSCC(Cc1ccccc1)C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc3ccccc3)N
  • InChI=1S/C31H38N2O3S3/c1-37-18-17-28(32)23-39-38-22-27(19-24-11-5-2-6-12-24)30(34)33-29(20-25-13-7-3-8-14-25)31(35)36-21-26-15-9-4-10-16-26/h2-16,27-29H,17-23,32H2,1H3,(H,33,34)/t27?,28-,29-/m0/s1
  • Key:QXXMSEVVNUSHKJ-KEKPXRHTSA-N
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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 buildup 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, such as proglumide. [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] [12]

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. [13] [14] Consequently, even though RB-101 is able to produce potent analgesic effects via the opioid system, it is unlikely to be addictive. [15] [16]

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. [17] 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. [18]

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. [19] [20] [21] [22] [23]

See also

Related Research Articles

Endorphins are endogenous opioid neuropeptides and peptide hormones in humans and other animals. They are produced and stored in the pituitary gland. The classification of molecules as endorphins is based on their pharmacological activity, as opposed to a specific chemical formulation.

Opioid Psychoactive chemical

Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use disorder, reversing opioid overdose, and suppressing cough. Extremely potent opioids such as carfentanil are approved only for veterinary use. Opioids are also frequently used non-medically for their euphoric effects or to prevent withdrawal. Opioids can cause death and have been used for executions in the United States.

Enkephalin Pentapeptide

An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin have been found, one containing leucine ("leu"), and the other containing methionine ("met"). Both are products of the proenkephalin gene.

<i>beta</i>-Endorphin Peptide hormone in Homo sapiens

Beta-Endorphin or β-Endorphin is an endogenous opioid neuropeptide and peptide hormone that is produced in certain neurons within the central nervous system and peripheral nervous system. It is one of three endorphins that are produced in humans, the others of which include α-endorphin and γ-endorphin.

Opioid peptide

Opioid peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble those of opiates. Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, and the control of food intake.

Endomorphin Chemical compound

Endomorphins are considered to be natural opioid neurotransmitters central to pain relief. The two known endomorphins, endomorphin-1 and endomorphin-2, are tetrapeptides, consisting of Tyr-Pro-Trp-Phe and Tyr-Pro-Phe-Phe amino acid sequences respectively. These sequences fold into tertiary structures with high specificity and affinity for the μ-opioid receptor, binding it exclusively and strongly. Bound μ-opioid receptors typically induce inhibitory effects on neuronal activity. Endomorphin-like immunoreactivity exists within the central and peripheral nervous systems, where endomorphin-1 appears to be concentrated in the brain and upper brainstem, and endomorphin-2 in the spinal cord and lower brainstem. Because endomorphins activate the μ-opioid receptor, which is the target receptor of morphine and its derivatives, endomorphins possess significant potential as analgesics with reduced side effects and risk of addiction.

Opiorphin Endogenous chemical compound first isolated from human saliva

Opiorphin is an endogenous chemical compound first isolated from human saliva. Initial research with mice shows the compound has a painkilling effect greater than that of morphine. It works by stopping the normal breakup of enkephalins, natural pain-killing opioids in the spinal cord. It is a relatively simple molecule consisting of a five-amino acid polypeptide, Gln-Arg-Phe-Ser-Arg (QRFSR).

Met-enkephalin Chemical compound

Met-enkephalin, also known as metenkefalin (INN), sometimes referred to as opioid growth factor (OGF), is a naturally occurring, endogenous opioid peptide that has opioid effects of a relatively short duration. It is one of the two forms of enkephalin, the other being leu-enkephalin. The enkephalins are considered to be the primary endogenous ligands of the δ-opioid receptor, due to their high potency and selectivity for the site over the other endogenous opioids.

δ-opioid receptor Opioid receptor named for the mouse vas deferens, where it was first characterized

The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the δ-opioid receptor is largely expressed vary from species model to species model. In humans, the δ-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.

Proglumide Chemical compound

Proglumide (Milid) is a drug that inhibits gastrointestinal motility and reduces gastric secretions. It acts as a cholecystokinin antagonist, which blocks both the CCKA and CCKB subtypes. It was used mainly in the treatment of stomach ulcers, although it has now been largely replaced by newer drugs for this application.

Racecadotril Chemical compound

Racecadotril, also known as acetorphan, is an antidiarrheal medication which acts as a peripheral enkephalinase inhibitor. Unlike other opioid medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect — it reduces the secretion of water and electrolytes into the intestine. It is available in France and other European countries as well as most of South America and some South East Asian countries, but not in the United States. It is sold under the tradename Hidrasec, among others. Thiorphan is the active metabolite of racecadotril, which exerts the bulk of its inhibitory actions on enkephalinases.

A cholecystokinin receptor antagonist is a specific type of receptor antagonist which blocks the receptor sites for the peptide hormone cholecystokinin (CCK).

CI-988

CI-988 (PD-134,308) is a drug which acts as a cholecystokinin antagonist, selective for the CCKB subtype. In animal studies it showed anxiolytic effects and potentiated the analgesic action of both morphine and endogenous opioid peptides, as well as preventing the development of tolerance to opioids and reducing symptoms of withdrawal. Consequently, it was hoped that it might have clinical applications for the treatment of pain and anxiety in humans, but trial results were disappointing with only minimal therapeutic effects observed even at high doses. The reason for the failure of CI-988 and other CCKB antagonists in humans despite their apparent promise in pre-clinical animal studies is unclear, although poor pharmacokinetic properties of the currently available drugs are a possible explanation, and CCKB antagonists are still being researched for possible uses as adjuvants to boost the activity of other drugs.

Ecadotril Chemical compound

Ecadotril is a neutral endopeptidase inhibitor and determined by the presence of peptidase family M13 as a neutral endopeptidase inhibited by phosphoramidon. Ecadotril is the (S)-enantiomer of racecadotril. NEP-like enzymes include the endothelin-converting enzymes. The peptidase M13 family believed to activate or inactivate oligopeptide (pro)-hormones such as opioid peptides, neprilysin is another member of this group, in the case of the metallopeptidases and aspartic, the nucleophiles clan or family for example MA, is an activated water molecule. The peptidase domain for members of this family also contains a bacterial member and resembles that of thermolysin the predicted active site residues for members of this family and thermolysin occur in the motif HEXXH. Thermolysin complexed with the inhibitor (S)-thiorphan are isomeric thiol-containing inhibitors of endopeptidase EC 24-11.

(+)-Naloxone

(+)-Naloxone (dextro-naloxone) is a drug which is the opposite enantiomer of the opioid antagonist drug (−)-naloxone. Unlike (-)-naloxone, (+)-naloxone has no significant affinity for opioid receptors, but instead has been discovered to act as a selective antagonist of Toll-like receptor 4. This receptor is involved in immune system responses, and activation of TLR4 induces glial activation and release of inflammatory mediators such as TNF-α and Interleukin-1.

Kelatorphan

Kelatorphan is a drug which acts as a powerful and complete inhibitor of nearly all of the enzymes responsible for catabolism of the endogenous enkephalins, including neutral endopeptidase (NEP), dipeptidyl peptidase III (DPP3), aminopeptidase N (APN), and angiotensin-converting enzyme (ACE). In mice, with the intracerebroventricular co-administration of a 50 µg dose of kelatorphan (this route is necessary because kelatorphan is incapable of crossing the blood-brain-barrier) hence alongside exogenous [Met]enkephalin (ED50 approximately 10 ng), it potentiated the analgesic effects of the latter by 50,000 times. Kelatorphan also displays potent antinociceptive effects alone, and does not depress respiration, although at high doses it actually increases it.

An enkephalinase inhibitor is a type of enzyme inhibitor which inhibits one or more members of the enkephalinase class of enzymes that break down the endogenous enkephalin opioid peptides. Examples include racecadotril, ubenimex (bestatin), RB-101, and D-phenylalanine, as well as the endogenous opioid peptides opiorphin and spinorphin. It also includes RB-3007, Semax and Selank. Analgesic, anticraving, antidepressant, anxiolytic, and antidiarrheal effects are common properties of enkephalinase inhibitors.

Spinorphin Chemical compound

Spinorphin is an endogenous, non-classical opioid peptide of the hemorphin family first isolated from the bovine spinal cord (hence the prefix spin-) and acts as a regulator of the enkephalinases, a class of enzymes that break down endogenous the enkephalin peptides. It does so by inhibiting the enzymes aminopeptidase N (APN), dipeptidyl peptidase III (DPP3), angiotensin-converting enzyme (ACE), and neutral endopeptidase (NEP). Spinorphin is a heptapeptide and has the amino acid sequence Leu-Val-Val-Tyr-Pro-Trp-Thr (LVVYPWT). It has been observed to possess antinociceptive, antiallodynic, and anti-inflammatory properties. The mechanism of action of spinorphin has not been fully elucidated (i.e., how it acts to inhibit the enkephalinases), but it has been found to act as an antagonist of the P2X3 receptor, and as a weak partial agonist/antagonist of the FP1 receptor.

RB-120

RB-120 is an orally active analog of the drug RB-101. It acts as an enkephalinase inhibitor, which is used in scientific research. Via intravenous administration, it is approximately three times as potent as RB-101 or twice as potent as the isolated (S,S) isomer of RB101. However, via i.p. administration it is approximately twice as potent as racemic RB-101 and about as potent as the isolated (S,S) isomer of RB101. During i.v. administration RB120 is approximately twice as weak as morphine in terms of analgesia, however it is 16x weaker during i.p. and p.o. administration.

RB-3007 Chemical compound

RB-3007 is an orally active analogue of RB-101. It acts as an enkephalinase inhibitor, which is used in scientific research.

References

  1. ↑ Roques BP (April 1992). "Peptidomimetics as receptors agonists or peptidase inhibitors: A structural approach in the field of enkephalins, ANP and CCK". Biopolymers. 32 (4): 407–10. doi:10.1002/bip.360320417. PMID   1320419.
  2. ↑ Noble F, Soleilhac JM, Soroca-Lucas E, Turcaud S, Fournie-Zaluski MC, Roques BP (April 1992). "Inhibition of the enkephalin-metabolizing enzymes by the first systemically active mixed inhibitor prodrug RB 101 induces potent analgesic responses in mice and rats". The Journal of Pharmacology and Experimental Therapeutics . 261 (1): 181–90. PMID   1560364.
  3. ↑ Fournié-Zaluski MC, Coric P, Turcaud S, Lucas E, Noble F, Maldonado R, Roques BP (Jun 1992). "Mixed inhibitor-prodrug" as a new approach toward systemically active inhibitors of enkephalin-degrading enzymes". Journal of Medicinal Chemistry. 35 (13): 2473–81. doi:10.1021/jm00091a016. PMID   1352352.
  4. ↑ Noble F, Smadja C, Roques BP (December 1994). "Role of endogenous cholecystokinin in the facilitation of mu-mediated antinociception by delta-opioid agonists". The Journal of Pharmacology and Experimental Therapeutics. 271 (3): 1127–34. PMID   7996417.
  5. ↑ Valverde O, Maldonado R, Fournie-Zaluski MC, Roques BP (July 1994). "Cholecystokinin B antagonists strongly potentiate antinociception mediated by endogenous enkephalins". The Journal of Pharmacology and Experimental Therapeutics. 270 (1): 77–88. PMID   8035345.
  6. ↑ Honore P, Buritova J, Fournié-Zaluski MC, Roques BP, Besson JM (April 1997). "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". The Journal of Pharmacology and Experimental Therapeutics. 281 (1): 208–17. PMID   9103499.
  7. ↑ Jutkiewicz EM, Torregrossa MM, Sobczyk-Kojiro K, et al. (February 2006). "Behavioral and neurobiological effects of the enkephalinase inhibitor RB101 relative to its antidepressant effects". European Journal of Pharmacology. 531 (1–3): 151–9. doi:10.1016/j.ejphar.2005.12.002. PMC   1828120 . PMID   16442521.
  8. ↑ Jutkiewicz EM (2007). "RB101-mediated Protection of Endogenous Opioids: Potential Therapeutic Utility?" (PDF). CNS Drug Reviews. 13 (2): 192–205. doi:10.1111/j.1527-3458.2007.00011.x. PMC   6726351 . PMID   17627672.
  9. ↑ Maldonado R, Valverde O, Ducos B, Blommaert AG, Fournie-Zaluski MC, Roques BP (March 1995). "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 . 114 (5): 1031–9. doi:10.1111/j.1476-5381.1995.tb13309.x. PMC   1510310 . PMID   7780637.
  10. ↑ Ruiz F, Fournié-Zaluski MC, Roques BP, Maldonado R (September 1996). "Similar decrease in spontaneous morphine abstinence by methadone and RB 101, an inhibitor of enkephalin catabolism". British Journal of Pharmacology. 119 (1): 174–82. doi:10.1111/j.1476-5381.1996.tb15691.x. PMC   1915744 . PMID   8872371.
  11. ↑ Roques BP, Noble F (November 1996). "Association of enkephalin catabolism inhibitors and CCK-B antagonists: a potential use in the management of pain and opioid addiction". Neurochemical Research. 21 (11): 1397–410. doi:10.1007/bf02532381. PMID   8947930.
  12. ↑ Cordonnier L, Sanchez M, Roques BP, Noble F (May 2007). "Blockade of morphine-induced behavioral sensitization by a combination of amisulpride and RB101, comparison with classical opioid maintenance treatments". British Journal of Pharmacology. 151 (1): 94–102. doi:10.1038/sj.bjp.0707195. PMC   2012985 . PMID   17351659.
  13. ↑ Noble F, Turcaud S, Fournié-Zaluski MC, Roques BP (November 1992). "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. 223 (1): 83–9. doi:10.1016/0014-2999(92)90821-K. PMID   1478260.
  14. ↑ Noble F, Coric P, Turcaud S, Fournié-Zaluski MC, Roques BP (March 1994). "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. 253 (3): 283–7. doi:10.1016/0014-2999(94)90203-8. PMID   8200422.
  15. ↑ Noble F, Fournié-Zaluski MC, Roques BP (January 1993). "Unlike morphine the endogenous enkephalins protected by RB101 are unable to establish a conditioned place preference in mice". European Journal of Pharmacology. 230 (2): 139–49. doi:10.1016/0014-2999(93)90796-K. PMID   8422896.
  16. ↑ Stein, Christoph, ed. (1999). Opioids in pain control : basic and clinical aspects. Cambridge, UK: Cambridge University Press. ISBN   978-0521622691.
  17. ↑ Boudinot E, Morin-Surun M, Foutz AS, Fournié-Zaluski M, Roques BP, Denavit-Saubié M (February 2001). "Effects of the potent analgesic enkephalin-catabolizing enzyme inhibitors RB101 and kelatorphan on respiration". Pain. 90 (1–2): 7–13. doi:10.1016/S0304-3959(00)00382-1. PMID   11166965.
  18. ↑ Nieto MM, Wilson J, Walker J, et al. (September 2001). "Facilitation of enkephalins catabolism inhibitor-induced antinociception by drugs classically used in pain management". Neuropharmacology. 41 (4): 496–506. doi:10.1016/S0028-3908(01)00077-6. PMID   11543770.
  19. ↑ Noble F, Smadja C, Valverde O, et al. (December 1997). "Pain-suppressive effects on various nociceptive stimuli (thermal, chemical, electrical and inflammatory) of the first orally active enkephalin-metabolizing enzyme inhibitor RB 120". Pain. 73 (3): 383–91. doi:10.1016/S0304-3959(97)00125-5. PMID   9469529.
  20. ↑ Le Guen S, Mas Nieto M, Canestrelli C, et al. (July 2003). "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. 104 (1–2): 139–48. doi:10.1016/S0304-3959(02)00486-4. PMID   12855323.
  21. ↑ Le Guen S, Mas Nieto M, Canestrelli C, Chen H, Fournié-Zaluski MC, Cupo A, Maldonado R, Roques BP, Noble F (July 2003). "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. 104 (1–2): 139–48. doi:10.1016/S0304-3959(02)00486-4. PMID   12855323.
  22. ↑ Noble F, Roques BP (February 2007). "Protection of endogenous enkephalin catabolism as natural approach to novel analgesic and antidepressant drugs". Expert Opinion on Therapeutic Targets. 11 (2): 145–59. doi:10.1517/14728222.11.2.145. PMID   17227231.
  23. ↑ Thanawala V, Kadam VJ, Ghosh R (October 2008). "Enkephalinase inhibitors: potential agents for the management of pain". Current Drug Targets. 9 (10): 887–94. doi:10.2174/138945008785909356. PMID   18855623.
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