1.0 2011-09-21 01:51:59 UTC 2015-07-21 06:59:39 UTC FDB029215 Dynorphin A Dynorphin A is an endogenous opioid peptide that produces non-opioid receptor-mediated neural excitation.Dynorphin induces calcium influx via voltage-sensitive calcium channels in sensory neurons by activating bradykinin receptors. This action of dynorphin at bradykinin receptors is distinct from the primary signaling pathway activated by bradykinin and underlies the hyperalgesia produced by pharmacological administration of dynorphin by the spinal route in rats and mice. Blockade of spinal B1 or B2 receptor also reverses persistent neuropathic pain but only when there is sustained elevation of endogenous spinal dynorphin, which is required for maintenance of neuropathic pain. These data reveal a mechanism for endogenous dynorphin to promote pain through its agonist action at bradykinin receptors and suggest new avenues for therapeutic intervention. Dynorphin A is a form of dynorphin.Dynorphins 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 a/b-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."This 32-amino acid molecule consists of both dynorphin A and dynorphin B.Dynorphin A, dynorphin B, and big dynorphin all contain a high proportion of basic amino acid residues, in particular lysine and arginine (29.4%, 23.1%, and 31.2% basic residues, respectively), as well as many hydrophobic residues (41.2%, 30.8%, and 34.4% hydrophobic residues, respectively). Although dynorphins are found widely distributed in the CNS, they have the highest concentrations in the hypothalamus, medulla, pons, midbrain, and spinal cord. Dynorphins are stored in large (80-120 nm diameter) dense-core vesicles that are considerably larger than vesicles storing neurotransmitters. These large dense-core vesicles differ from small synaptic vesicles in that a more intense and prolonged stimulus is needed to cause the large vesicles to release their contents into the synaptic cleft. Dense-core vesicle storage is characteristic of opioid peptides storage. The first clues to the functionality of dynorphins came from Goldstein et al. in their work with opioid peptides. The group discovered an endogenous opioid peptide in the porcine pituitary that proved difficult to isolate. By sequencing the first 13 amino acids of the peptide, they created a synthetic version of the peptide with a similar potency to the natural peptide. Goldstein et al. applied the synthetic peptide to the guinea ileum longitudinal muscle and found it to be an extraordinarily potent opioid peptide. The peptide was called dynorphin (from the Greek dynamis=power) to describe its potency. Dynorphins exert their effects primarily through the κ-opioid receptor (KOR), a G-protein-coupled receptor. Two subtypes of KORs have been identified: K1 and K2. Although KOR is the primary receptor for all dynorphins, the peptides do have some affinity for the μ-opioid receptor (MOR), d-opioid receptor (DOR), N-methyl-D-aspartic acid (NMDA)-type glutamate receptor . Different dynorphins show different receptor selectivities and potencies at receptors. Big dynorphin and dynorphin A have the same selectivity for human KOR, but dynorphin A is more selective for KOR over MOR and DOR than is big dynorphin. Big dynorphin is more potent at KORs than is dynorphin A. Both big dynorphin and dynorphin A are more potent and more selective than dynorphin B (from wiki) [HMDB] dynorphin A 1-17 Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln C69H116N23O13 1475.8056 1474.912295913 (2S)-6-amino-2-{[(2S)-1-[(2R)-2-[(2S)-2-[(2R)-2-[(2R)-2-[(2R)-2-[(2R)-2-(2-{2-[(2R)-2-amino-3-(4-hydroxyphenyl)propanamido]acetamido}acetamido)-3-phenylpropanamido]-4-methylpentanamido]-5-carbamimidamidopentanamido]-5-carbamimidamidopentanamido]-3-methylpentanamido]-5-[(azaniumylmethanimidoyl)amino]pentanoyl]pyrrolidin-2-yl]formamido}-N-[(1S)-1-carbamoyl-3-methylbutyl]hexanamide (2S)-6-amino-2-{[(2S)-1-[(2R)-2-[(2S)-2-[(2R)-2-[(2R)-2-[(2R)-2-[(2R)-2-(2-{2-[(2R)-2-amino-3-(4-hydroxyphenyl)propanamido]acetamido}acetamido)-3-phenylpropanamido]-4-methylpentanamido]-5-carbamimidamidopentanamido]-5-carbamimidamidopentanamido]-3-methylpentanamido]-5-[(ammoniomethanimidoyl)amino]pentanoyl]pyrrolidin-2-yl]formamido}-N-[(1S)-1-carbamoyl-3-methylbutyl]hexanamide 80448-90-4 CCC(C)[C@H](NC(=O)[C@@H](CCCNC(N)=N)NC(=O)[C@@H](CCCNC(N)=N)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](CC1=CC=CC=C1)NC(=O)CNC(=O)CNC(=O)[C@H](N)CC1=CC=C(O)C=C1)C(=O)N[C@H](CCCNC([NH3+])=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(N)=O InChI=1S/C69H115N23O13/c1-7-41(6)56(65(104)88-49(22-15-31-81-69(77)78)66(105)92-32-16-23-53(92)64(103)87-46(19-11-12-28-70)60(99)89-50(57(72)96)33-39(2)3)91-61(100)48(21-14-30-80-68(75)76)85-59(98)47(20-13-29-79-67(73)74)86-62(101)51(34-40(4)5)90-63(102)52(36-42-17-9-8-10-18-42)84-55(95)38-82-54(94)37-83-58(97)45(71)35-43-24-26-44(93)27-25-43/h8-10,17-18,24-27,39-41,45-53,56,93H,7,11-16,19-23,28-38,70-71H2,1-6H3,(H2,72,96)(H,82,94)(H,83,97)(H,84,95)(H,85,98)(H,86,101)(H,87,103)(H,88,104)(H,89,99)(H,90,102)(H,91,100)(H4,73,74,79)(H4,75,76,80)(H4,77,78,81)/p+1/t41?,45-,46+,47-,48-,49-,50+,51-,52-,53+,56+/m1/s1 ZIHYAUCIMOSJIH-QGLXRRFISA-O belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues. Polypeptides Organic compounds Organic Polymers Polypeptides Aromatic heteromonocyclic compounds 1-hydroxy-2-unsubstituted benzenoids Alpha amino acid amides Amphetamines and derivatives Aralkylamines Azacyclic compounds Carbonyl compounds Carboximidamides Guanidines Hydrocarbon derivatives Isoleucine and derivatives Leucine and derivatives Monoalkylamines N-acyl amines N-acyl-alpha amino acids and derivatives N-acylpyrrolidines Organic cations Organic oxides Organopnictogen compounds Peptides Phenylalanine and derivatives Primary carboxylic acid amides Proline and derivatives Pyrrolidinecarboxamides Secondary carboxylic acid amides Tertiary carboxylic acid amides Tyrosine and derivatives 1-hydroxy-2-unsubstituted benzenoid Alpha peptide Alpha-amino acid amide Alpha-amino acid or derivatives Amine Amino acid or derivatives Amphetamine or derivatives Aralkylamine Aromatic heteromonocyclic compound Azacycle Benzenoid Carbonyl group Carboxamide group Carboximidamide Carboxylic acid derivative Fatty acyl Fatty amide Guanidine Hydrocarbon derivative Isoleucine or derivatives Leucine or derivatives Monocyclic benzene moiety N-acyl-alpha amino acid or derivatives N-acyl-amine N-acylpyrrolidine N-substituted-alpha-amino acid Organic cation Organic nitrogen compound Organic oxide Organic oxygen compound Organoheterocyclic compound Organonitrogen compound Organooxygen compound Organopnictogen compound Phenol Phenylalanine or derivatives Polypeptide Primary aliphatic amine Primary amine Primary carboxylic acid amide Proline or derivatives Pyrrolidine Pyrrolidine carboxylic acid or derivatives Pyrrolidine-2-carboxamide Secondary carboxylic acid amide Tertiary carboxylic acid amide Tyrosine or derivatives Solid logp -0.62 ALOGPS logs -4.94 ALOGPS solubility 1.73e-02 g/l ALOGPS logp -4.9 ChemAxon pka_strongest_acidic 9.43 ChemAxon pka_strongest_basic 12.37 ChemAxon iupac (2S)-6-amino-2-{[(2S)-1-[(2R)-2-[(2S)-2-[(2R)-2-[(2R)-2-[(2R)-2-[(2R)-2-(2-{2-[(2R)-2-amino-3-(4-hydroxyphenyl)propanamido]acetamido}acetamido)-3-phenylpropanamido]-4-methylpentanamido]-5-carbamimidamidopentanamido]-5-carbamimidamidopentanamido]-3-methylpentanamido]-5-[(azaniumylmethanimidoyl)amino]pentanoyl]pyrrolidin-2-yl]formamido}-N-[(1S)-1-carbamoyl-3-methylbutyl]hexanamide ChemAxon average_mass 1475.8056 ChemAxon mono_mass 1474.912295913 ChemAxon smiles CCC(C)[C@H](NC(=O)[C@@H](CCCNC(N)=N)NC(=O)[C@@H](CCCNC(N)=N)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](CC1=CC=CC=C1)NC(=O)CNC(=O)CNC(=O)[C@H](N)CC1=CC=C(O)C=C1)C(=O)N[C@H](CCCNC([NH3+])=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(N)=O ChemAxon formula C69H116N23O13 ChemAxon inchi InChI=1S/C69H115N23O13/c1-7-41(6)56(65(104)88-49(22-15-31-81-69(77)78)66(105)92-32-16-23-53(92)64(103)87-46(19-11-12-28-70)60(99)89-50(57(72)96)33-39(2)3)91-61(100)48(21-14-30-80-68(75)76)85-59(98)47(20-13-29-79-67(73)74)86-62(101)51(34-40(4)5)90-63(102)52(36-42-17-9-8-10-18-42)84-55(95)38-82-54(94)37-83-58(97)45(71)35-43-24-26-44(93)27-25-43/h8-10,17-18,24-27,39-41,45-53,56,93H,7,11-16,19-23,28-38,70-71H2,1-6H3,(H2,72,96)(H,82,94)(H,83,97)(H,84,95)(H,85,98)(H,86,101)(H,87,103)(H,88,104)(H,89,99)(H,90,102)(H,91,100)(H4,73,74,79)(H4,75,76,80)(H4,77,78,81)/p+1/t41?,45-,46+,47-,48-,49-,50+,51-,52-,53+,56+/m1/s1 ChemAxon inchikey ZIHYAUCIMOSJIH-QGLXRRFISA-O ChemAxon polar_surface_area 613.99 ChemAxon refractivity 432.34 ChemAxon polarizability 159.41 ChemAxon rotatable_bond_count 48 ChemAxon acceptor_count 23 ChemAxon donor_count 23 ChemAxon physiological_charge 5 ChemAxon formal_charge 1 ChemAxon Specdb::MsMs 297727 Specdb::MsMs 297728 Specdb::MsMs 297729 Specdb::MsMs 2756296 Specdb::MsMs 2756297 Specdb::MsMs 2756298 Specdb::NmrOneD 98158 Specdb::NmrOneD 98159 Specdb::NmrOneD 98160 Specdb::NmrOneD 98161 Specdb::NmrOneD 98162 Specdb::NmrOneD 98163 Specdb::NmrOneD 98164 Specdb::NmrOneD 98165 Specdb::NmrOneD 98166 Specdb::NmrOneD 98167 Specdb::NmrOneD 98168 Specdb::NmrOneD 98169 Specdb::NmrOneD 98170 Specdb::NmrOneD 98171 Specdb::NmrOneD 98172 Specdb::NmrOneD 98173 Specdb::NmrOneD 98174 Specdb::NmrOneD 98175 Specdb::NmrOneD 98176 Specdb::NmrOneD 98177 HMDB12935