title: Design, synthesis and pharmacological characterization of endomorphin analogues with non-cyclic amino acid residues in position 2.
abstract: A series of endomorphin-1 (EM-1) and endomorphin-2 (EM-2) analogues, containing non-cyclic amino acids (Ala, D-Ala, beta-Ala, NMeAla, D-NMeAla or Sar) instead of Pro in position 2 was synthesized, where NMeAla = N-methylalanine and Sar = N-methylglycine, sarcosine. The opioid activity profiles of these peptides were determined in mu and delta opioid receptor (MOR and DOR)-representative binding assays and bioassays in vitro, as well as in the mouse hot-plate test in vivo. Finally, the degradation rates of all analogues in the presence of either rat brain homogenate or selected proteolytic enzymes were determined. Analogues of EM-2 were generally more potent than the respective analogues of EM-1. EM-2 analogues with D-Ala or D-NMeAla were about twofold more potent than the parent peptide and were least prone to degradation by brain homogenate, dipeptydyl peptidase IV and aminopeptidase M. In the in vivo test, [D-Ala(2)]EM-2 and [D-NMeAla(2)]EM-2 showed much higher analgesic potency than EM-2 which confirmed the usefulness of structural modifications in obtaining new leads for pain-relief therapeutics.
authors.affiliation: Department of Biomolecular Chemistry, Medical University, Lodz, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Perlikowska
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
authors.forename: Anna
authors.initials: A
authors.lastname: Wyrebska
authors.forename: Jeroen
authors.initials: J
authors.lastname: Poels
authors.forename: Jozef
authors.initials: J
authors.lastname: Vanden Broeck
authors.forename: Geza
authors.initials: G
authors.lastname: Toth
authors.forename: Martin
authors.initials: M
authors.lastname: Storr
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: do Rego
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D018826:CD13 Antigens / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D011485:Protein Binding; D051381:Rats; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; C105294:endomorphin 2; D018826:CD13 Antigens; D018819:Dipeptidyl Peptidase 4