title: Pharmacological properties of novel cyclic pentapeptides with µ-opioid receptor agonist activity.
abstract: In our previous paper we have reported the synthesis and biological activity of a cyclic analog, Tyr-c(D-Lys- Phe-Phe-Asp)-NH2, based on endomorphin-2 (EM-2) structure. This analog displayed high affinity for the µ-opioid receptor, was much more stable than EM-2 in rat brain homogenate and showed remarkable antinociceptive activity after intracerebroventricular (i.c.v.) injection. Even more importantly, the cyclic analog elicited weak analgesia also after peripheral administration, giving evidence that it was able to cross, at least to some extent, the blood-brain barrier (BBB). Here we describe further modifications of this analog aimed at enhancing brain delivery by increasing lipophilicity. Two new cyclic pentapeptides, Tyr-c(D-Lys-D-1-Nal-Phe-Asp)-NH2 and Tyr-c(D-Lys-D-2-Nal-Phe-Asp)-NH2 (where 1-Nal=1- naphthyl-3-alanine, 2-Nal=2-naphthyl-3-alanine) were synthesized and evaluated in biological assays. Both analogs showed high µ-opioid receptor affinity and agonist activity and were stable in the rat brain homogenates. Unfortunately, the increase of lipophilicity was achieved at the expense of water solubility. The analog with D-2-Nal residue showed strong analgesic effect when given i.c.v. but could not be tested after intravenous (i.v.) administration where higher concentrations of the compound are required. However, this analog showed inhibitory effect on gastrointestinal (GI) motility in vivo, providing an interesting approach to the development of peripherally restricted agents that could be useful for studying gastrointestinal disorders in animal models.
authors.forename: Renata
authors.initials: R
authors.lastname: Perlikowska
authors.forename: Justyna
authors.initials: J
authors.lastname: Piekielna
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: do-Rego
authors.forename: Geza
authors.initials: G
authors.lastname: Toth
authors.forename: Tomasz
authors.initials: T
authors.lastname: Janecki
authors.affiliation: Department of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland. anna.janecka@umed.lodz.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D010456:Peptides, Cyclic; D017450:Receptors, Opioid, mu