caa a22 4500 477125719 CHVBK 20180405111648.0 cr unu---uuuuu 170330e19970601xx s 000 0 eng 10.1023/A:1012185919153 doi (NATIONALLICENCE)springer-10.1023/A:1012185919153 Dynorphin Peptides: Antagonists of Melanocortin Receptors [Elektronische Daten] [J. Quillan, Wolfgang Sadée] Purpose. To identify possible targets that mediate the non-opioid effects of dynorphin A (DynA), effects that include inflammation and aggravation of traumatic nerve injury. Methods. We examined dynorphin peptides for functional interaction with the closely related melanocortin (MC) system. Results. DynA-(l-13)NH2 and other related opioid dynorphin peptides antagonize the human MC1, MC3 and MC4 receptors, and an amphibian MC receptor, with dissociation constants (Kd's) of 40 to 150 nM. The affinity of dynorphin's interaction with MC receptors is therefore greater than with other previously proposed non-opioid targets of dynorphin, which require micromolar concentrations. Dynorphin also antagonizes the adrenocorticotropic hormone (ACTH; MC2) receptor and an MC-like receptor endogenous to COS-7 cells, but with lower efficacy. In contrast DynA had no effect on seven control receptors and was only weakly effective at two others. Metabolites of dynorphin derived from cleavage of the amino terminal Tyr residue, such as DynA(2-17), lack opioid activity yet still produce a number of well established non-opioid effects. These des-Tyr derivatives also antagonized each of the five MC receptors examined. Conclusions. DynA peptides were found to antagonize MC receptorsin vitro with potencies that parallel those reported for pharmacological non-opioid effects of dynorphins in vivo. The combination of DynA and its active metabolites may reach levels sufficient to inhibit MC receptors physiologically. Dynorphin inhibition of MC receptors could prove to be an example of crosstalk between two distinct yet phylogenetically related neurotransmitter systems. Plenum Publishing Corporation, 1997 opioid peptides nationallicence [des-Tyr]dynorphin nationallicence non-opioid dynorphin effects nationallicence melanocortin receptors nationallicence receptor cross-reactivity nationallicence melanocortin peptides nationallicence α-melanocyte-stimulating hormone (α-MSH) nationallicence adrenocorticotropic hormone (ACTH) nationallicence tolerance nationallicence dependence nationallicence shock nationallicence trauma nationallicence Quillan J. Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, University of California Medical Center, 94143-0446, San Francisco, California aut Sadée Wolfgang Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, University of California Medical Center, 94143-0446, San Francisco, California aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/6(1997-06-01), 713-719 0724-8741 14:6<713 1997 14 11095 https://doi.org/10.1023/A:1012185919153 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012185919153 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Quillan J. Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, University of California Medical Center, 94143-0446, San Francisco, California aut NATIONALLICENCE 700 1- Sadée Wolfgang Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, University of California Medical Center, 94143-0446, San Francisco, California aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/6(1997-06-01), 713-719 0724-8741 14:6<713 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer