title: N-terminal guanidinylation of the cyclic 1,4-ureido-deltorphin analogues: the synthesis, receptor binding studies, and resistance to proteolytic digestion.
abstract: The synthesis of a series of N-guanidinylated cyclic ureidopeptides, analogues of 1,4-ureido-deltorphin/dermorphine tetrapeptide is described. The δ- and μ-opioid receptor affinity of new guanidinylated analogues and their non-guanidinylated precursors was determined by the displacement radioligand binding experiments. Our results indicate that the guanidinylation of cyclic 1,4-ureidodeltorphin peptide analogues does not exhibit a uniform influence on the opioid receptor binding properties, similarly as reported earlier for some linear peptides. All analogues were also tested for their in vitro resistance to proteolysis during incubation with large excess of chymotrypsin, pepsin, and papain by means of mass spectroscopy. Guanidinylated ureidopeptides 1G-4G showed mixed μ agonist/δ agonist properties and high enzymatic stability indicating their potential as therapeutic agents for treatment of pain.
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, Warsaw, 01-793, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Bańkowski
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, Warsaw, 01-793, Poland.
authors.forename: Olga M
authors.initials: OM
authors.lastname: Michalak
authors.affiliation: Mossakowski Medical Research Centre Polish Academy of Sciences, Pawińskiego 5, 02-106, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Leśniak
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, Warsaw, 01-793, Poland.
authors.forename: Katarzyna E
authors.initials: KE
authors.lastname: Filip
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, Warsaw, 01-793, Poland.|Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Cmoch
authors.affiliation: Faculty of Chemistry, University of Wrocław, 14 F. Joliot-Curie Str., 50-383, Wrocław, Poland.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Szewczuk
authors.affiliation: Faculty of Chemistry, University of Wrocław, 14 F. Joliot-Curie Str., 50-383, Wrocław, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Stefanowicz
authors.affiliation: Faculty of Chemistry, Department of Chemistry, Warsaw University, Pasteura 1, 02-093, Warsaw, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Izdebski
mesh_terms: D000818:Animals; D002918:Chymotrypsin / Q000737:chemistry; D019791:Guanidine / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism*; D010206:Papain / Q000737:chemistry; D010434:Pepsin A / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis*; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C059567:deltorphin; D002918:Chymotrypsin; D010206:Papain; D010434:Pepsin A; D019791:Guanidine
keywords: binding to opioid receptors; cyclic opioid peptides; dermorphin/deltorphin analogues; peptide guanidinylation; stability to proteolytic enzymes