Of dynorphins

Several substituted analogues of dynorphin have shown moderate improvement in K-selectivity, including Ala -dynorphin Trp -dynorphin... 

Lee, E.D., Muck, W., Henion, J.D., Covey, T.R (1988). On-line capillary zone electrophoresis-ion spray tandem mass spectrometry for the determination of dynorphin. J. Chromatogr. 458, 313-321. 

Paterlini G, Portoghese P, Ferguson D. Molecular simulation of dynorphin A-(1—10) binding to extracellular loop 2 of the kappa opioid receptor. A model for receptor activation. J Med Chem 1997 40 3254-3262. 

J. Yu, E. R. Butelman, J. H. Woods, B. T. Chait, and M. J. Rreek. In Vitro Biotransformation of Dynorphin A (1-17) is Similar in Human and Rhesus Monkey Blood as Studied by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry. J. Pharmacol. Exp. Then, 279(1996) 507-514. 

S. Muller, A. Hutson, V. Arya, G. Hochhaus, Assessment of Complex Peptide Degradation Pathways via Structured Multicompartmental Modeling Approaches The Metabolism of Dynorphin Al-13 and Related Fragments in Human Plasma , J. Pharm. Sci. 1999, 88, 938-944 S. Muller, G. Hochhaus, Metabolism of Dynorphin A 1-13 in Human Blood and Plasma , Pharm. Res. 1995, 12, 1165- 1170. 

J. P. Meyer, T. J. Gillespie, S. Horn, V. J. Hruby, T. P. Davis, In vitro Stability of Some Reduced Peptide Bond Pseudopeptide Analogues of Dynorphin A , Peptides 1995, 16, 1215-1219. 

Prokai L, Zharikova AD. 1998. Identification of synaptic metabolites of dynorphin A (1-8) by electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 12 1796. 

Sandin J, Tan-No K, Kasakov L, Nylander I, Winter A, et al. 1997. Differential metabolism of dynorphins in substantia nigra, striatum, and hippocampus. Peptides 18 949. 

It is of historical interest to note that the disclosure of U-50488 occurred at roughly the same time as two chemically unrelated compounds which behave as poorly selective kappa agonist analgesics. These are the benzodiazepine, tifluadom (6) [17] and the amino-terminal nonapeptide fragment of dynorphin, Dyn (1-9), (7) (kappa A) = 0.21 nM, mu K = 3.6 nM delta K, = 3.2 nM) [18], which is thought to be the endogenous kappa opioid agonist. 

The EOPs have been directly implicated in the pathophysiology of TS syndrome. Haber and co-workers (1986) reported decreased levels of dynorphin A(l-17) immunoreactivity in striatal fibers projecting to the GP in postmortem material from a small number of Tour-ette s patients. This observation, coupled with the neu-roanatomic distribution of dynorphin, its broad range of motor and behavioral effects, and its modulatory interactions with striatal dopaminergic systems, suggest that dynorphin might have a key role in the patho-biology of TS. However, subsequent studies have failed to confirm these initial observations (van Wattum et al., 1999). 

In contrast to the analgesic role of leu- and met-enkephalin, an analgesic action of dynorphin A—through its binding to (kappa) opioid receptors—remains controversial. Dynorphin A is also found in the dorsal horn of the spinal cord, where it may play a critical role in the sensitization of nociceptive neurotransmission. Increased levels of dynorphin can be found in the dorsal horn after tissue injury and inflammation. This elevated dynorphin level is proposed to increase pain and induce a state of long-lasting hyperalgesia. The pronociceptive action of dynorphin in the spinal cord appears to be independent of the opioid receptor system but dependent on the activation of the bradykinin receptor. Moreover, dynorphin A can bind and activate the N -methyl-D-aspartate (NMDA) receptor complex, a site of action that is the focus of intense therapeutic development. 

Lai 3 et al Pronociceptive actions of dynorphin via bradykinin receptors. Neurosci Lett 2008 437 175. [PMID 18450375]... 

Wang Z et al Pronociceptive actions of dynorphin maintain chronic neuropathic pain. 3 Neurosci 2001 21 1779. [PMID ... 

The exact function of dynorphin is unknown, but evidence suggests that it is produced to counter the pleasurable effects of produced by cocaine and is, to some degree, neuroprotective.9 Some believe dynorphin may play an important role in determining an individual s risk for addiction. Blocking the actions of dynorphin helps to alleviate depression.10... 

Muller, S., A. Hutson,V. Arya, and G. Hochhaus. 1999. Assessment of complex peptide degradation pathways via structured multicompartmental modeling approaches the metabolism of dynorphin Al-13 and related fragments in human plasma [In Process Citation]. 

V. jV-Ethylmaleimide-Induced Nociceptive Behavior Mediated Through Inhibition of Dynorphin Degradation... 

Another set of evidence supports the notion on the pronociceptive functions of dynorphin A in the spinal cord. Behavioral hyperalgesia as a result of inflammation or tissue injury is accompanied by elevations in spinal dynorphin content... 

Iadarola, M. J., Brady, L. S., Draisci, G., and Dubner, R. (1988). Enhancement of dynorphin gene expression in spinal cord following experimental inflammation Stimulus specificity, behavioral parameters and opioid receptor binding. Pain 35, 313—326. 

Shukla, V. K., and Lemaire, S. (1994). Nonopioid effects of dynorphins Possible role of the NMDA receptor. Trends Pharmacol. Sci. 15, 420—424. 

Silberring, J., Castello, M. E., and Nyberg, F. (1992). Characterization of dynorphin A-converting enzyme in human spinal cord. An endoprotease related to a distinct conversion pathway for the opioid heptadecapeptide J. Biol. Chem. 267, 21324—21328. 

Silberring, J., Demuth, H. U., Brostedt, P., and Nyberg, F. (1993). Inhibition of dynorphin converting enzymes from human spinal cord by TV -peptidyl-O-acyl hydroxylamines. J. Biockem. 114, 648-651. 

Tan-No, K., Taira, A., Sakurada, T., Inoue, M., Sakurada, S., Tadano, T., Sato, T., Sakurada, C., Nylander, I., Silberring, J., Terenius, L., and Kisara, K. (1996). Inhibition of dynorphin-converting enzymes prolongs the antinociceptive effect of intrathecally administered dynorphin in the mouse formalin test. Eur.J. Pharmacol. 314, 61-67. 

---