title: Synthesis, biological activity and resistance to proteolytic digestion of new cyclic dermorphin/deltorphin analogues.
abstract: A series of novel cyclic ureidopeptides, analogues of dermorphine/deltorphine tetrapeptide, were synthesized by solid phase peptide synthesis and/or in solution. The antinociceptive activity of N-substituted amides 1-10 was evaluated using hot-plate and tail-flick tests. Analogue 1 showed significant, stronger than morphine, antinociceptive effect after systemic applications. All analogues were also tested for their in vitro resistance to proteolysis by means of mass spectroscopy and it was found that all substituted amides 1-10 showed full stability during incubation with large excess of chymotrypsin and pepsin. Compound 1 is a lead molecule for further evaluation.
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland. k.bankowski@ifarm.eu
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Bańkowski
authors.forename: Ewa
authors.initials: E
authors.lastname: Witkowska
authors.forename: Olga M
authors.initials: OM
authors.lastname: Michalak
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Sidoryk
authors.forename: Ewa
authors.initials: E
authors.lastname: Szymanek
authors.forename: Bożena
authors.initials: B
authors.lastname: Antkowiak
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Paluch
authors.forename: Katarzyna E
authors.initials: KE
authors.lastname: Filip
authors.forename: Marek
authors.initials: M
authors.lastname: Cebrat
authors.forename: Bartosz
authors.initials: B
authors.lastname: Setner
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Szewczuk
authors.forename: Piotr
authors.initials: P
authors.lastname: Stefanowicz
authors.forename: Piotr
authors.initials: P
authors.lastname: Cmoch
authors.forename: Jan
authors.initials: J
authors.lastname: Izdebski
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002918:Chymotrypsin / Q000378:metabolism; D006358:Hot Temperature / Q000009:adverse effects; D006868:Hydrolysis; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D007211:Indoles; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018847:Opioid Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010434:Pepsin A / Q000378:metabolism; D059748:Proteolysis; D021241:Spectrometry, Mass, Electrospray Ionization; D013343:Styrenes
chemical_list: D000701:Analgesics, Opioid; C093843:ESI 4; D007211:Indoles; D009842:Oligopeptides; D018847:Opioid Peptides; D013343:Styrenes; C059567:deltorphin; C030058:dermorphin; D002918:Chymotrypsin; D010434:Pepsin A