 | |
| Names | |
|---|---|
| IUPAC name L-tyrosyl-glycyl-glycyl-L-phenylalanyl-L-leucyl-L-arginyl-L-arginyl-L-isoleucyl-L-arginyl-L-prolyl-L-lysyl-L-leucyl-L-lysyl-L-tryptophyl-L-alpha-aspartyl-L-asparagyl-L-glutaminyl-L-lysyl-L-arginyl-L-tyrosyl-glycyl-glycyl-L-phenylalanyl-L-leucyl-L-arginyl-L-arginyl-L-glutaminyl-L-phenylalanyl-L-lysyl-L-valyl-L-valyl-L-threonine | |
Other names
| |
| Identifiers | |
3D model (JSmol) | |
| ChemSpider | |
| |
| |
| Properties | |
| C185H292N58O41 | |
| Molar mass | 3985 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Big dynorphin is anendogenous opioidpeptide of thedynorphin family. It forms when aprecursor proteinprodynorphin is not fully processed, resulting in a 32-amino acidmolecule containing bothdynorphin A anddynorphin B sequences. It has theamino 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.[2][3]
Big dynorphin is a highlyefficiacious principalendogenousagonist at the humanκ-opioid receptor (KOR).[2][4] It produces one of the strongest responses atGPR139 receptor among dynorphins.[5] Additionally, it uniquely modulatesNMDA receptor and potentiatesacid-sensing ion channel 1a (ASIC1a).[6][7]
It plays a role inpain and stress responses. It exhibits bothanelgesic andpro-nociceptive properties.[8] In mice it modulatesmemory andlearning, and hasanxiolytic properties, contributing to homeostatic regulation ofopioid signaling in thecentral nervous system.[3][6][8]
Big dynorphin1-32 is the primaryendogenously documented big dynorphin form, but various shorter big dynorphin fragments have been synthesized for research purposes. These include (2-32), (2-26), (9-19) forms.[7]
Big dynorphin is generated through theproteolytic processing ofprodynorphin (PDYN), a 26-kilodaltonprecursor protein byproprotein convertase 1.[9] The synthesis occurs within theneuronalcell body throughtranslation of prodynorphinmRNA. Following translation, prodynorphin undergoes sequential processing byproprotein convertases, primarily PC1/3 andPC2, as well as thecysteine proteasecathepsin L.[4][10]
Under normal circumstances, in the presence ofcarboxypeptidase E, prodynorphin is fully processed by sequential cleavage at dibasicamino acid sites to generate individual dynorphin peptides:dynorphin A1-17,dynorphin B, andα-neoendorphin.[9] Big dynorphin forms when this proteolytic processing is incomplete, typically resulting from insufficient proprotein convertase activity or altered intracellularcalcium levels duringneurotransmitter release events.[11] The 32-amino acid peptide comprises the completedynorphin A sequence (residues 1-17) joined to the completedynorphin B sequence, with twoC-terminal amino acids.
Big dynorphin release occurs primarily in acalcium-dependent manner throughexocytosis oflarge dense core vesicles in thepresynaptic terminal.[12] Big dynorphinimmunoreactivity has been detected in regions such as thenucleus accumbens,caudate nucleus, andhippocampus, with significant levels detected incerebrospinal fluid. The ratio of big dynorphin to dynorphin B in human brain tissue is approximately 1:3.[4]
| Target | Affinity (Ki, nM) |
|---|---|
| KOR | 0.198 (Ki) 0.741 (EC50Tooltip half-maximal effective concentration) 159% (EmaxTooltip maximal efficacy) |
| MOR | 14 (Ki) 87 (EC50) 115% (Emax) |
| DOR | 43 (Ki) 119 (EC50) 100% (Emax) |
| NOP | 105 |
| ASIC1 | 26-211 (EC50) |
| Notes: The smaller the value, the more avidly the drug interacts with the site. Max. stimulation is shown as percentage of that induced by dyn A1-17Sources:[4][7][13] | |
Big dynorphin acts as apotentfull agonist at the humanκ-opioid receptor (KOR), exhibiting extremely high relativeefficacy at this target.[4] In one binding assay it demonstrated similaraffinity todynorphin A, but about 14 to 32-fold higher potency to activateG proteins than otherdynorphin peptides.[4] In contrast, other studies have suggested similar or higher potencies of other dynorphins.[14][15]
Big dynorphin is also anagonist of otheropioid receptors, It is 70-fold selective towards KOR overμ-opioid receptors (MOR) and 200 overδ-opioid receptor (DOR).[4]
In olderguinea-pigileumbioassay measuring nativereceptor function, big dynorphin shows approximately 10-20-fold reduced potency relative to dynorphin A, possibly due to conformational constraints of the largerpeptide affecting receptor binding in peripheral tissue. This discrepancy suggests that big dynorphin's efficacy in human KOR systems may not translate directly to potency in peripheral tissue.[16]
Big dynorphin could theoretically produce some of the classical pharmacological effects associated with KOR agonism such asdysphoria,dissociation, andsedation, but this has not been directly evaluated.[4][17] Similarly biased signaling of big dynorphin at KOR has not yet been assessed.[18]
Big dynorphin is one of the activators of theGPR139, aG protein-coupled receptor (GPCR), recently deorphanized as a dynorphin receptor. In a wideneuropeptide library screen it exhibited one of the highestefficacies among prodynorphin-derived peptides.[5]
At low concentrations, dynorphins predominantly activate canonical opioid receptors (KOR, MOR, DOR), while at higher concentrations, they additionally recruit GPR139. This receptor couples toGq/11G protein-mediated signaling, which is mechanistically opposite to theGi/o inhibitory signaling of classicalopioid receptors. This permits GPR139 to function as a molecular homeostatic brake: when dynorphin reaches high concentrations during intensestress orpain, simultaneousGPR139 activation counteracts excessiveopioid receptor signaling throughexcitatorysignaling pathways, preventing pathological over-inhibition of neuronal activity.[5]
Big dynorphin modulatesNMDA receptors, producing effects that areantagonist-insensitive to opioid receptor blockade.[6]Intracerebroventricular injection of big dynorphin producedmemory enhancement in passive avoidance tests, enhanced locomotor activity in theopen field test, andanxiolytic-like effects that were blocked by theNMDA receptor antagonistMK-801 but resistant tonor-BNI, a selective KOR antagonist.[6]
In contrast, dynorphin A anddynorphin B at similar doses producedanalgesia (mediated by opioid receptors) but did not produce the NMDA-dependent memory enhancement, anxiolysis, orlocomotor stimulation.[6]
Suggested mechanisms are interaction with thepolyaminebinding site or theNR2B subunit.[6] The molecular basis for this atypical activity may involve the extendedC-terminal region unique to big dynorphin, which contains multiple basic residues (arginine andlysine).[19]
Big dynorphin is a potent endogenous modulator of theacid-sensing ion channel 1a (ASIC1a) and current rescue following steady-state desensitization.[7][13] In comparison, dynorphin A exhibits a approximately 1000-fold lower potency than big dynorphin at this target.[7]
Big dynorphin potentiates ASIC1a current through a mechanism independent of both opioid andbradykinin receptor signaling.[7] The potency correlates with big dynorphin's features, particularly its high net positive charge (9+) and abundance of arginine residues (6 total), withresidues Arg6, Arg7. Big dynorphin rescues proton-gated currents and promotesacidosis-inducedneuronal cell death in culturedcortical neurons, implicating it in pathological conditions involving cellular acidification andexcitotoxicity.[20]
Like otherdynorphin peptides, big dynorphin can produceanalgesic effects throughκ-opioid receptor (KOR) activation atspinalnociceptive sites.[17] However, atsupraspinal levels through non-opioid mechanisms involvingNMDA receptor modulation andASIC1a activation, big dynorphin can producepro-nociceptive effects, enhancing pain sensitivity in both acute andchronic pain states.[8]
Big dynorphin has been shown to enhancelearning in rodent models through NMDA receptor modulation.[6] This contrasts with theamnestic effects typically associated withopioid receptoragonists and otherdynorphins. The mechanism may involve modulation of theNR2B subunit, a modulator ofcorticalsynaptic plasticity andlong-term potentiation (LTP).[6]
Big dynorphin is upregulated inspinal cord injury andchronic pain states, where excessive big dynorphin production through bothopioid and non-opioid receptor mechanisms contribute toneuronal death,neuroinflammation, and pain chronification.[7]
In contrary, big dynorphin exhibits neuroprotective properties againstamyloid-β (Aβ) accumulation inAlzheimer's disease. It reduces thehydrophobicity and slows the aggregation kinetics of Aβ40, the most abundant amyloid species, resulting in around 2-fold reduction in amyloid aggregation compared to Aβ alone.[21] In humanneuroblastomacell cultures, big dynorphin pre-incubated with Aβ40 significantly increased cell viability to compared to Aβ40 alone.[21] The neuroprotective mechanism involves big dynorphin'scationicamino acid residues stabilizing negatively charged regions of Aβ, preventing theβ-sheet transition and maintaining Aβ in anα-helical conformation.[21] These findings suggest therapeutic potential for big dynorphin-derivedpeptides in Alzheimer's disease treatment.
Principal endogenous agonists at κ receptor
Peptide sequence
YGGFLRRIRPKLKWDNQKRYGGFLRRQFKVVT
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