Opiorphin

Last updated
Opiorphin [1]
Opiorphin.png
Names
IUPAC name
(2S,5S,8S,11S,14S)-14,17-diamino-8-benzyl-2,11-bis(3-guanidinopropyl)-5-(hydroxymethyl)-4,7,10,13,17-pentaoxo-3,6,9,12-tetraazaheptadecan-1-oic acid
Other names
Gln-Arg-Phe-Ser-Arg; L-Glutaminyl-L-arginyl-L-phenylalanyl-L-seryl-L-arginine
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
PubChem CID
  • InChI=1S/C29H48N12O8/c30-17(10-11-22(31)43)23(44)38-18(8-4-12-36-28(32)33)24(45)40-20(14-16-6-2-1-3-7-16)25(46)41-21(15-42)26(47)39-19(27(48)49)9-5-13-37-29(34)35/h1-3,6-7,17-21,42H,4-5,8-15,30H2,(H2,31,43)(H,38,44)(H,39,47)(H,40,45)(H,41,46)(H,48,49)(H4,32,33,36)(H4,34,35,37)/t17-,18-,19-,20-,21-/m0/s1 X mark.svgN
    Key: TWWFCOBVAKAKIT-SXYSDOLCSA-N X mark.svgN
  • InChI=1/C29H48N12O8/c30-17(10-11-22(31)43)23(44)38-18(8-4-12-36-28(32)33)24(45)40-20(14-16-6-2-1-3-7-16)25(46)41-21(15-42)26(47)39-19(27(48)49)9-5-13-37-29(34)35/h1-3,6-7,17-21,42H,4-5,8-15,30H2,(H2,31,43)(H,38,44)(H,39,47)(H,40,45)(H,41,46)(H,48,49)(H4,32,33,36)(H4,34,35,37)/t17-,18-,19-,20-,21-/m0/s1
    Key: TWWFCOBVAKAKIT-SXYSDOLCBM
  • O=C([C@H](CO)NC([C@H](CC1=CC=CC=C1)NC([C@H](CCCNC(N)=N)NC([C@H](CCC(N)=O)N)=O)=O)=O)N[C@H](C(O)=O)CCCNC(N)=N
Properties
C29H48N12O8
Molar mass 692.779 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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. [2] 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). [3] [4] [5] [6] [7] [8] [9] [10]

Opiorphin pentapeptide originates from the N-terminal region of the protein PROL1 (proline-rich, lacrimal 1). [3] Opiorphin inhibits three proteases: neutral ecto-endopeptidase (MME), ecto-aminopeptidase N (ANPEP) [3] and perhaps also a dipeptidyl peptidase DPP3. [8] Such action extends the duration of enkephalin effect where the natural pain killers are released physiologically in response to specific potentially painful stimuli, in contrast with administration of narcotics, which floods the entire body and causes many undesirable adverse reactions, including addiction liability and constipation. [11] [12] In addition, opiorphin may exert anti-depressive [13] [14] and antipanic action. [15]

Therapeutic application of opiorphin in humans would require modifying the molecule to avoid its rapid degradation in the intestine and its poor penetration of the blood–brain barrier. [11] [12] This modification is done in the body by transformation of N-terminal glutamine into pyroglutamate. This form preserves the analgesic properties of opiorphin but with increased pharmaceutical stability. [16]

See also

Related Research Articles

Endorphins are peptides produced in the brain that block the perception of pain and increase feelings of wellbeing. They are produced and stored in the pituitary gland of the brain. Endorphins are endogenous painkillers often produced in the brain and adrenal medulla during physical exercise, and inhibit pain, muscle cramps, and relieve stress.

Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neo-endorphin. Depolarization of a neuron containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal. Occasionally, prodynorphin is not fully processed, leading to the release of “big dynorphin.” “Big Dynorphin” is a 32-amino acid molecule consisting of both dynorphin A and dynorphin B.

<span class="mw-page-title-main">Enkephalin</span> 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 humans

beta-Endorphin (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.

<span class="mw-page-title-main">Opioid peptide</span> Class of peptides that bind to opioid receptors

Opioid peptides or opiate 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, control of food intake, and the rewarding effects of alcohol and nicotine.

<span class="mw-page-title-main">Nociceptin</span> Chemical compound

Nociceptin/orphanin FQ (N/OFQ), a 17-amino acid neuropeptide, is the endogenous ligand for the nociceptin receptor. Nociceptin acts as a potent anti-analgesic, effectively counteracting the effect of pain-relievers; it's activation is associated with brain functions such as pain sensation and fear learning.

<span class="mw-page-title-main">Endomorphin</span> 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.

Na<sub>v</sub>1.7 Protein-coding gene in the species Homo sapiens

Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of neurons: the nociceptive (pain) neurons at dorsal root ganglion (DRG) and trigeminal ganglion and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.

<span class="mw-page-title-main">Met-enkephalin</span> 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.

DAMGO is a synthetic opioid peptide with high μ-opioid receptor specificity. It was synthesized as a biologically stable analog of δ-opioid receptor-preferring endogenous opioids, leu- and met-enkephalin. Structures of DAMGO bound to the µ opioid receptor reveal a very similar binding pose to morphinans.

<span class="mw-page-title-main">RB-101</span> Chemical compound

RB-101 is a drug that acts as an enkephalinase inhibitor, which is used in scientific research.

<span class="mw-page-title-main">Tail flick test</span> Pain response test

The tail flick test is a test of the pain response in animals, similar to the hot plate test. It is used in basic pain research and to measure the effectiveness of analgesics, by observing the reaction to heat. It was first described by D'Amour and Smith in 1941.

The hot plate test is a test of the pain response in animals, similar to the tail flick test. Both hot plate and tail-flick methods are used generally for centrally acting analgesic, while peripherally acting drugs are ineffective in these tests but sensitive to acetic acid-induced writhing test.

<span class="mw-page-title-main">Kelatorphan</span> Chemical compound

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.

<span class="mw-page-title-main">Spinorphin</span> 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.

<span class="mw-page-title-main">Tynorphin</span> Synthetic opioid chemical compound

Tynorphin is a synthetic opioid peptide which is a potent and competitive inhibitor of the enkephalinase class of enzymes which break down the endogenous enkephalin peptides. It specifically inactivates dipeptidyl aminopeptidase III (DPP3) with very high efficacy, but also inhibits neutral endopeptidase (NEP), aminopeptidase N (APN), and angiotensin-converting enzyme (ACE) to a lesser extent. It has a pentapeptide structure with the amino acid sequence Val-Val-Tyr-Pro-Trp (VVYPW).

Oxytocinase is a type of enzyme that metabolizes the endogenous neuropeptide, oxytocin. The most well-characterized oxytocinase is leucyl/cystinyl aminopeptidase, which is also an enkephalinase. Other oxytocinases are also known. During pregnancy, oxytocinase plays a role in balancing concentration of oxytocin by degrading the oxytocin produced by the fetus, as production of oxytocin increases with growth of fetus. One study found that concentration level of oxytocinase increased progressively with gestational age until labor, which indicates that pregnancy development can be statistically evaluated by comparing oxytocinase levels.

<span class="mw-page-title-main">RB-120</span> Chemical compound

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.

<span class="mw-page-title-main">RB-3007</span> 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. ↑ Opiorphin at Sigma-Aldrich
  2. ↑ Rougeot C, Robert F, Menz L, Bisson JF, Messaoudi M (August 2010). "Systemically active human opiorphin is a potent yet non-addictive analgesic without drug tolerance effects". J. Physiol. Pharmacol. 61 (4): 483–490. PMID   20814077.
  3. 1 2 3 Dickinson DP, Thiesse M (April 1996). "cDNA cloning of an abundant human lacrimal gland mRNA encoding a novel tear protein". Curr. Eye Res. 15 (4): 377–386. doi:10.3109/02713689608995828. PMID   8670737.
  4. ↑ Andy Coghlan (November 13, 2006). "Natural-born painkiller found in human saliva". New Scientist. Archived from the original on 2007-01-27.
  5. ↑ "Natural chemical 'beats morphine'". BBC News. November 14, 2006.
  6. ↑ Mary Beckman (November 13, 2006). "Prolonging Painkillers". ScienceNOW.
  7. ↑ Stanović S, Boranić M, Petrovecki M, et al. (2000). "Thiorphan, an inhibitor of neutral endopeptidase/enkephalinase (CD10/CALLA) enhances cell proliferation in bone marrow cultures of patients with acute leukemia in remission". Haematologia (Budap). 30 (1): 1–10. doi:10.1163/15685590051129814. PMID   10841318.
  8. 1 2 Thanawala V, Kadam VJ, Ghosh R (October 2008). "Enkephalinase inhibitors: potential agents for the management of pain". Curr Drug Targets. 9 (10): 887–894. doi:10.2174/138945008785909356. PMID   18855623.
  9. ↑ Davies KP (March 2009). "The role of opiorphins (endogenous neutral endopeptidase inhibitors) in urogenital smooth muscle biology". J Sex Med. 6 Suppl 3: 286–291. doi:10.1111/j.1743-6109.2008.01186.x. PMC   2864530 . PMID   19267851.
  10. ↑ Tian XZ, Chen J, Xiong W, He T, Chen Q (July 2009). "Effects and underlying mechanisms of human opiorphin on colonic motility and nociception in mice". Peptides. 30 (7): 1348–1354. doi:10.1016/j.peptides.2009.04.002. PMID   19442408. S2CID   32291165.
  11. 1 2 Rougeot C, Robert F, Menz L, Bisson JF, Messaoudi M (August 2010). "Systemically active human opiorphin is a potent yet non-addictive analgesic without drug tolerance effects" (PDF). J. Physiol. Pharmacol. 61 (4): 483–490. PMID   20814077.
  12. 1 2 Popik P, Kamysz E, Kreczko J, Wróbel M (November 2010). "Human opiorphin: the lack of physiological dependence, tolerance to antinociceptive effects and abuse liability in laboratory mice". Behav. Brain Res. 213 (1): 88–93. doi:10.1016/j.bbr.2010.04.045. PMID   20438769. S2CID   32205999.
  13. ↑ Javelot H, Messaoudi M, Garnier S, Rougeot C (June 2010). "Human opiorphin is a naturally occurring antidepressant acting selectively on enkephalin-dependent delta-opioid pathways" (PDF). J. Physiol. Pharmacol. 61 (3): 355–362. PMID   20610867.
  14. ↑ Yang QZ, Lu SS, Tian XZ, Yang AM, Ge WW, Chen Q (February 2011). "The antidepressant-like effect of human opiorphin via opioid-dependent pathways in mice". Neurosci. Lett. 489 (2): 131–135. doi:10.1016/j.neulet.2010.12.002. PMID   21145938. S2CID   22544303.
  15. ↑ Maraschin, Jhonatan Christian; Rangel, Marcel Pereira; Bonfim, Antonio Joaquim; Kitayama, Mariana; Graeff, Frederico Guilherme; Zangrossi Jr., Hélio; Audi, Elisabeth Aparecida (2016-02-01). "Opiorphin causes a panicolytic-like effect in rat panic models mediated by μ-opioid receptors in the dorsal periaqueductal gray". Neuropharmacology. 101: 264–270. doi:10.1016/j.neuropharm.2015.09.008. PMID   26363194. S2CID   34867419.
  16. ↑ Sitbon, Philippe; Van Elstraete, Alain; Hamdi, Leila; Juarez-Perez, Victor; Mazoit, Jean-Xavier; Benhamou, Dan; Rougeot, Catherine (2016-11-01). "STR-324, a Stable Analog of Opiorphin, Causes Analgesia in Postoperative Pain by Activating Endogenous Opioid Receptor-dependent Pathways". Anesthesiology. 125 (5): 1017–1029. doi:10.1097/ALN.0000000000001320. ISSN   1528-1175. PMID   27571257. S2CID   36827893.
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