title: Synthesis and biological evaluation of cyclic endomorphin-2 analogs.
abstract: In our previous paper we reported synthesis and biological activity of two cyclic analogs of endomorphin-2 (EM-2): Tyr-c(Lys-Phe-Phe-Asp)-NH(2) and Tyr-c(Asp-Phe-Phe-Lys)-NH(2), achieved by making an amid bond between Lys and Asp side-chains. The first analog did not bind to the mu-opioid receptor, the affinity of the second one was very low. In the present study, we describe the synthesis of four novel cyclic analogs of similar structure, but with d-amino acids in position 2 (D-Lys or D-Asp). All new analogs displayed high affinity for the mu-opioid receptor, were much more stable than EM-2 in rat brain homogenate and showed remarkable antinociceptive activity after intracerebroventricular (i.c.v.) administration. Analgesic effect of the most potent cyclic analog, Tyr-c(D-Lys-Phe-Phe-Asp)NH(2) was much stronger and longer lasting than that of EM-2. This analog elicited analgesia also after peripheral administration and this effect was reversed by concomitant i.c.v. injection of the mu-opioid antagonist, beta-funaltrexamine, which indicated that antinociception was mediated by the mu-opioid receptor in the brain. Central action of the cyclic analog gives evidence that it was able to cross the blood-brain barrier, most likely due to the increased lipophilicity. Our results demonstrate that cyclization might be a promising strategy to enhance bioavailability of peptides and may serve a role in the development of novel endomorphin analogs with increased therapeutic potential.
authors.affiliation: Department of Biomolecular Chemistry, Medical University, Lodz, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Perlikowska
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: do-Rego
authors.forename: Aurore
authors.initials: A
authors.lastname: Cravezic
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
authors.forename: Anna
authors.initials: A
authors.lastname: Wyrebska
authors.forename: Geza
authors.initials: G
authors.lastname: Toth
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
mesh_terms: D000595:Amino Acid Sequence; D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004723:Endorphins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D014020:Tissue Extracts / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D004723:Endorphins; D009292:Narcotic Antagonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D014020:Tissue Extracts; C105294:endomorphin 2; D009271:Naltrexone; C024524:beta-funaltrexamine