Dynorphin B

Last updated
Dynorphin B [1]
Dynorphin B.svg
Names
Other names
Dynorphin B-13; Rimorphin
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
  • InChI=1S/C74H115N21O17/c1-40(2)34-53(91-68(107)54(36-44-18-10-8-11-19-44)86-58(100)39-84-57(99)38-85-62(101)48(76)35-46-25-27-47(97)28-26-46)67(106)89-51(24-17-33-83-74(80)81)63(102)87-50(23-16-32-82-73(78)79)64(103)90-52(29-30-56(77)98)65(104)92-55(37-45-20-12-9-13-21-45)69(108)88-49(22-14-15-31-75)66(105)93-59(41(3)4)70(109)94-60(42(5)6)71(110)95-61(43(7)96)72(111)112/h8-13,18-21,25-28,40-43,48-55,59-61,96-97H,14-17,22-24,29-39,75-76H2,1-7H3,(H2,77,98)(H,84,99)(H,85,101)(H,86,100)(H,87,102)(H,88,108)(H,89,106)(H,90,103)(H,91,107)(H,92,104)(H,93,105)(H,94,109)(H,95,110)(H,111,112)(H4,78,79,82)(H4,80,81,83)/t43-,48+,49+,50+,51+,52+,53+,54+,55+,59+,60+,61+/m1/s1 X mark.svgN
    Key: AGTSSZRZBSNTGQ-ITZCFHCWSA-N X mark.svgN
  • InChI=1/C74H115N21O17/c1-40(2)34-53(91-68(107)54(36-44-18-10-8-11-19-44)86-58(100)39-84-57(99)38-85-62(101)48(76)35-46-25-27-47(97)28-26-46)67(106)89-51(24-17-33-83-74(80)81)63(102)87-50(23-16-32-82-73(78)79)64(103)90-52(29-30-56(77)98)65(104)92-55(37-45-20-12-9-13-21-45)69(108)88-49(22-14-15-31-75)66(105)93-59(41(3)4)70(109)94-60(42(5)6)71(110)95-61(43(7)96)72(111)112/h8-13,18-21,25-28,40-43,48-55,59-61,96-97H,14-17,22-24,29-39,75-76H2,1-7H3,(H2,77,98)(H,84,99)(H,85,101)(H,86,100)(H,87,102)(H,88,108)(H,89,106)(H,90,103)(H,91,107)(H,92,104)(H,93,105)(H,94,109)(H,95,110)(H,111,112)(H4,78,79,82)(H4,80,81,83)/t43-,48+,49+,50+,51+,52+,53+,54+,55+,59+,60+,61+/m1/s1
    Key: AGTSSZRZBSNTGQ-ITZCFHCWBN
  • [H]/N=C(\N)/NCCC[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CCCN/C(=N/[H])/N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)CNC(=O)CNC(=O)[C@H](Cc3ccc(cc3)O)N
Properties
C74H115N21O17
Molar mass 1570.8354
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 ?)

Dynorphin B, also known as rimorphin, [2] is a form of dynorphin and an endogenous opioid peptide with the amino acid sequence Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr. Dynorphin B is generated as a proteolytic cleavage product of leumorphin, which in turn is a cleavage product of preproenkephalin B (prodynorphin).[ citation needed ]

Contents


Dynorphin B has an identical N-terminal sequence, but different C-terminal sequence to dynorphin A. In an alanine scan of the non-glycine residues of dynorphin B, it was discovered that Tyr1 and Phe4 residues are critical for both opioid receptor affinity and κ-opioid receptor agonist potency, Arg6 and Arg7 promote κ-opioid affinity and Lys10 contributes to the opioid receptor affinity. [3]

Inducers of dynorphin B

Cannabinoid CP55,940 and △9-tetrahydrocannabinol (△9-THC) can induce the release of dynorphin B, which in return acts as an agonist of κ-opioid receptors, resulting in the production of antinociception. [4] Similarly, Tyr-D-Arg-Phe-Sar (TAPS) is capable of promoting a release of dynorphin B through the simulation of μ1-opioid receptors, causing a production of antinociception. [5] The antinociceptive effect produced by dynorphin B allows for spinal analgesia.

See also

Related Research Articles

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-neoendorphin. 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 as ligands 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.

β-Endorphin Peptide hormone in humans

β-Endorphin (beta-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">Dermorphin</span> Opioid agonist peptide compound

Dermorphin is a hepta-peptide first isolated from the skin of South American frogs belonging to the genus Phyllomedusa. The peptide is a natural opioid that binds as an agonist with high potency and selectivity to mu opioid receptors. Dermorphin is about 30–40 times more potent than morphine, but theoretically may be less likely to produce drug tolerance and addiction due to its high potency. The amino acid sequence of dermorphin is H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2.

<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">Endomorphin</span> Chemical compound

Endomorphins are considered to be natural opioid neuropeptides 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.

<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.

<span class="mw-page-title-main">Nociceptin receptor</span> Protein-coding gene in the species Homo sapiens

The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors. Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.

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

Dynorphin A is a dynorphin, an endogenous opioid peptide that activates the κ-opioid receptor. Its amino acid sequence is Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys.

Leu-enkephalin is an endogenous opioid peptide neurotransmitter with the amino acid sequence Tyr-Gly-Gly-Phe-Leu that is found naturally in the brains of many animals, including humans. It is one of the two forms of enkephalin; the other is met-enkephalin. The tyrosine residue at position 1 is thought to be analogous to the 3-hydroxyl group on morphine. Leu-enkephalin has agonistic actions at both the μ- and δ-opioid receptors, with significantly greater preference for the latter. It has little to no effect on the κ-opioid receptor.

Big dynorphin is an endogenous opioid peptide of the dynorphin family that is composed of both dynorphin A and dynorphin B. Big dynorphin has the amino acid sequence: Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-Lys-Arg-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr. It has nociceptive and anxiolytic-like properties, as well as effects on memory in mice.

<span class="mw-page-title-main">DADLE</span> Synthetic opioid analgesic peptide

DADLE is a synthetic opioid peptide with analgesic properties. Although it is often considered a selective δ-opioid receptor agonist, it also binds to the μ1 subtype of μ-opioid receptors.

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

Adrenorphin, also sometimes referred to as metorphamide, is an endogenous, C-terminally amidated, opioid octapeptide (Tyr-Gly-Gly-Phe-Met-Arg-Arg-Val-NH2, YGGFMRRV-NH2) that is produced from proteolytic cleavage of proenkephalin A and is widely distributed throughout the mammalian brain. It was named based on the fact that it was originally detected in human phaeochromocytoma tumour derived from the adrenal medulla, and was subsequently found in normal human and bovine adrenal medulla as well. Adrenorphin exhibits potent opioid activity, acting as a balanced μ- and κ-opioid receptor agonist while having no effects on δ-opioid receptors. It possesses analgesic and respiratory depressive properties.

Neoendorphins are a group of endogenous opioid peptides derived from the proteolytic cleavage of prodynorphin. They include α-neoendorphin and β-neoendorphin. The α-neoendorphin is present in greater amounts in the brain than β-neoendorphin. Both are products of the dynorphin gene, which also expresses dynorphin A, dynorphin A-(1-8), and dynorphin B. These opioid neurotransmitters are especially active in Central Nervous System receptors, whose primary function is pain sensation. These peptides all have the consensus amino acid sequence of Try-Gly-Gly-Phe-Met (met-enkephalin) or Tyr-Gly-Gly-Phe-Leu ( leu-enkephalin). Binding of neoendorphins to opioid receptors (OPR), in the dorsal root ganglion (DRG) neurons results in the reduction of time of calcium-dependent action potential. The α-neoendorphins bind OPRD1(delta), OPRK1(kappa), and OPRM1 (mu) and β-neoendorphin bind OPRK1.

<span class="mw-page-title-main">Hemorphin-4</span> Endogenous opioid peptide

Hemorphin-4 is an endogenous opioid peptide of the hemorphin family which possesses antinociceptive properties and is derived from the β-chain of hemoglobin in the bloodstream. It is a tetrapeptide with the amino acid sequence Tyr-Pro-Trp-Thr. Hemorphin-4 has affinities for the μ-, δ-, and κ-opioid receptors that are in the same range as the structurally related β-casomorphins, although affinity to the κ-opioid receptor is markedly higher in comparison. It acts as an agonist at these sites. Hemorphin-4 also has inhibitory effects on angiotensin-converting enzyme (ACE), and as a result, may play a role in the regulation of blood pressure. Notably, inhibition of ACE also reduces enkephalin catabolism.

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

Biphalin is a dimeric enkephalin endogenous peptide (Tyr-D-Ala-Gly-Phe-NH)2 composed of two tetrapeptides derived from enkephalins, connected 'tail-to-tail' by a hydrazide bridge. The presence of two distinct pharmacophores confers on biphalin a high affinity for both μ and δ opioid receptors (with an EC50 of about 1–5 nM for both μ and δ receptors), therefore it has analgesic activity. Biphalin presents a considerable antinociceptive profile. In fact, when administered intracerebroventricularly in mice, biphalin displays a potency almost 7-fold greater than that of the ultra-potent alkaloid agonist, etorphine and 7000-fold greater than morphine; biphalin and morphine were found to be equipotent after intraperitoneal administration. The extraordinary in vivo potency shown by this compound is coupled with low side-effects, in particular, to produce no dependency in chronic use. For these reasons, several efforts have been carried out in order to obtain more information about structure-activity relationship (SAR). Results clearly indicate that, at least for μ receptor binding, the presence of two pharmacophores is not necessary; Tyr1 is indispensable for analgesic activity, while replacing Phe at the position 4 and 4' with non-aromatic, but lipophilic amino acids does not greatly change the binding properties and in general 4,4' positions are found to be important to design biphalin analogues with increased potency and modified μ/δ selectivity. The hydrazide linker is not fundamental for activity or binding, and it can be conveniently substituted by different conformationally constrained cycloaliphatic diamine linkers.

<span class="mw-page-title-main">CR665</span> Chemical compound

CR665 (H-D-Phe-D-Phe-D-Nle-D-Arg-NH-4-Picolyl), also known by the previous developmental code names FE-200665 and JNJ-38488502, is an all D-amino acid peptide that acts as a peripherally restricted κ-opioid receptor agonist. The selectivity for FE 200665 is 1/16,900/84,600 for the human κ, μ, and δ opioid receptors, respectively. The dose of FE 200665 required to produce motor impairment was 548 times higher than the dose required for antinociceptive activity. It is being developed for use by Cara Therapeutics under the code name CR665.

Leumorphin, also known as dynorphin B1–29, is a naturally occurring endogenous opioid peptide. Derived as a proteolytic cleavage product of residues 226-254 of prodynorphin, leumorphin is a nonacosapeptide and has the sequence Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr-Arg-Ser-Gln-Glu-Asp-Pro-Asn-Ala-Tyr-Ser-Gly-Glu-Leu-Phe-Asp-Ala. It can be further reduced to dynorphin B and dynorphin B-14 by pitrilysin metallopeptidase 1, an enzyme of the endopeptidase family. Leumorphin behaves as a potent and selective κ-opioid receptor agonist, similarly to other endogenous opioid peptide derivatives of prodynorphin.

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

Quadazocine (WIN-44,441) is an opioid antagonist of the benzomorphan family which is used in scientific research. It acts as a silent antagonist at all three of the major opioid receptors—μ, κ, and δ, but with a significant preference in affinity for the μ receptor and the κ2 subtype. As such, it has been touted as a "κ2-selective" antagonist, though this is not entirely accurate on account of its similar affinity for the μ receptor. As would be expected, quadazocine reverses the effects of opioid agonists like morphine and fentanyl in animals.

<span class="mw-page-title-main">Endomorphin-2</span> Chemical compound

Endomorphin-2 (EM-2) is an endogenous opioid peptide and one of the two endomorphins. It has the amino acid sequence Tyr-Pro-Phe-Phe-NH2. It is a high affinity, highly selective agonist of the μ-opioid receptor, and along with endomorphin-1 (EM-1), has been proposed to be the actual endogenous ligand of this receptor (that is, rather than the endorphins). Like EM-1, EM-2 produces analgesia in animals, but whereas EM-1 is more prevalent in the brain, EM-2 is more prevalent in the spinal cord. In addition, the action of EM-2 differs from that of EM-1 somewhat, because EM-2 additionally induces the release of dynorphin A and [Met]enkephalin in the spinal cord and brain by an unknown mechanism, which in turn activate the κ- and δ-opioid receptors, respectively, and a portion of the analgesic effects of EM-2 is dependent on this action. Moreover, while EM-1 produces conditioned place preference, a measure of drug reward, EM-2 produces conditioned place aversion, an effect which is dynorphin A-dependent. Similarly to the case of EM-1, the gene encoding for EM-2 has not yet been identified.

References

  1. ↑ Dynorphin B - Compound Summary, PubChem.
  2. ↑ Paul V. Malven (12 January 1993). Mammalian Neuroendocrinology. CRC Press. p. 70. ISBN   978-0-8493-8757-9 . Retrieved 22 April 2012.
  3. ↑ Joshi, Anand A.; Murray, Thomas F.; Aldrich, Jane V. (September 2017). "Alanine scan of the opioid peptide dynorphin B amide". Biopolymers. 108 (5): e23026. doi:10.1002/bip.23026. PMC   6003702 . PMID   28464209.
  4. ↑ Houser, Susan J; Eads, Micah; Embrey, James P; Welch, Sandra P (February 2000). "Dynorphin B and spinal analgesia: induction of antinociception by the cannabinoids CP55,940, Δ9-THC and anandamide1Published on the World Wide Web on 18 January 2000.1". Brain Research. 857 (1–2): 337–342. doi:10.1016/S0006-8993(00)01981-8. PMID   10700588. S2CID   8616013.
  5. ↑ Mizoguchi, Hirokazu; Ito, Kanenori; Watanabe, Hiroyuki; Watanabe, Chizuko; Katsuyama, Sou; Fujimura, Tsutomu; Sakurada, Tsukasa; Sakurada, Shinobu (November 2006). "Contribution of spinal μ1-opioid receptors and dynorphin B to the antinociception induced by Tyr-d-Arg-Phe-Sar". Peptides. 27 (11): 2786–2793. doi:10.1016/j.peptides.2006.07.006. PMID   16919848. S2CID   1770295.


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