title: Synthesis and antinociceptive activity of cyclic endomorphin-2 and morphiceptin analogs.
abstract: Cyclic analogs of the opioid peptides endomorphin-2 and morphiceptin of the type Tyr-X-Phe-Phe-Y-NH2 and Tyr-X-Phe-D-Pro-Y-NH2 (X = Lys or Asp and Y = Lys or Asp), respectively, were synthesized in order to test their structure-activity relationships. Antinociceptive activity of the new analogs was assessed in the hot-plate test after intracerebroventricular administration in mice. The strong analgesic effect was observed for the analogs with Asp in position 2, while the analogs with Lys in the second position were inactive. Antinociception caused by Asp2 analogs was dose-dependent and reversed by the concomitant administration of the universal opioid antagonist naloxone and by the selective kappa antagonist, nor-BNI. However, receptor binding studies revealed poor affinity of all cyclic analogs at the mu-opioid receptor and no affinity at delta- and kappa-opioid receptors. It is most likely that the new cyclic analogs produced their antinociception by the release of dynorphin A, which subsequently acted on the kappa-opioid receptor.
authors.affiliation: Department of Medicinal Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland. ajanecka@zdn.am.lodz.pl
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
authors.forename: Rafal
authors.initials: R
authors.lastname: Kruszynski
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Jean
authors.initials: J
authors.lastname: Costentin
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: do-Rego
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004723:Endorphins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D004723:Endorphins; D009842:Oligopeptides; D011957:Receptors, Opioid; C105294:endomorphin 2; C028889:morphiceptin