title: Effect of 2',6'-dimethyl-L-tyrosine (Dmt) on pharmacological activity of cyclic endomorphin-2 and morphiceptin analogs.
abstract: This study reports the synthesis and biological evaluation of a series of new side-chain-to-side-chain cyclized endomorphin-2 (EM-2) and morphiceptin analogs of a general structure Tyr-c(Xaa-Phe-Phe-Yaa)NH(2) or Tyr-c(Xaa-Phe-D-Pro-Yaa)NH(2), respectively, where Xaa and Yaa were L/D Asp or L/D Lys. Further modification of these analogs was achieved by introduction of 2',6'-dimethyl-L-tyrosine (Dmt) instead of Tyr in position 1. Peptides were synthesized by solid phase method and cleaved from the resin by a microwave-assisted procedure. Dmt(1)-substituted analogs displayed high affinity at the μ-opioid receptors, remained intact after incubation with the rat brain homogenate and showed remarkable, long-lasting μ-opioid receptor-mediated antinociceptive activity after central, but not peripheral administration. Our results demonstrate that cyclization is a promising strategy in the development of new opioid analgesics, but further modifications are necessary to enhance the blood-brain barrier permeability.
authors: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
authors: Jakub
authors: J
authors: Fichna
authors: Renata
authors: R
authors: Perlikowska
authors: Anna
authors: A
authors: Wyrębska
authors: Katarzyna
authors: K
authors: Gach
authors: Justyna
authors: J
authors: Piekielna
authors: Jean Claude
authors: JC
authors: do-Rego
authors: Geza
authors: G
authors: Toth
authors: Alicja
authors: A
authors: Kluczyk
authors: Tomasz
authors: T
authors: Janecki
authors: Anna
authors: A
authors: Janecka
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004347:Drug Interactions; D004723:Endorphins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology*; D018847:Opioid Peptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C000597538:2',6'-dimethyltyrosyl-cyclo(lysyl-phenylalanyl-prolyl-aspartyl)amide; D004723:Endorphins; D009842:Oligopeptides; D018847:Opioid Peptides; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C076121:2',6'-dimethyltyrosine; C105294:endomorphin 2; D014443:Tyrosine; C028889:morphiceptin