title: Characterization of antinociceptive activity of novel endomorphin-2 and morphiceptin analogs modified in the third position.
abstract: In the present study we investigated and compared the in vivo analgesia of centrally administered endomorphin-2 and morphiceptin, and their analogs modified in position 3. Two series of analogs were synthesized by introducing unnatural aromatic amino acids in the D configuration: 3-(1-naphthyl)-D-alanine (D-1-Nal), 3-(2-naphthyl)-D-alanine (D-2-Nal), 3-(4-chlorophenyl)-D-alanine (D-ClPhe), 3-(3,4-dichlorophenyl)-D-alanine (D-Cl2Phe). Antinociceptive activity of endomorphin-2, morphiceptin, and their analogs was compared in the mouse hot-plate test, performed after i.c.v. administration of the peptides at a dose of 10 microg/animal. The best results were obtained for two morphiceptin analogs, [D-Phe3]morphiceptin and [D-1-Nal3]morphiceptin, which showed greatly improved analgesic activity, as compared to morphiceptin. In the endomorphin-2 series none of the modifications produced analogs more potent than the parent compound, but [D-1-Nal3]endomorphin-2 was the best analog. Antinociception induced by endomorphin-2 was reversed by concomitant i.c.v. administration of [D-Phe3]endomorphin-2, [D-2-Nal3]endomorphin-2, and [D-2-Nal3]morphiceptin, indicating that these analogs were weak mu-opioid antagonists.
authors.affiliation: Department of Medicinal Chemistry, Medical University of Lodz, Mazowiecka 6/8, Lodz 92215, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: do-Rego
authors.forename: Piotr
authors.initials: P
authors.lastname: Kosson
authors.forename: Jean
authors.initials: J
authors.lastname: Costentin
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
mesh_terms: D019943:Amino Acid Substitution; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004723:Endorphins / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000700:Analgesics; D004723:Endorphins; D009842:Oligopeptides; C105294:endomorphin 2; C028889:morphiceptin