Synthesis and activity of opioid peptidomimetics with β2- and β3-amino acids.

Abstract

Morphiceptin (Tyr-Pro-Phe-Pro-NH2) is a selective ligand of the mu opioid receptor, an important target in pain regulation. In this study, morphiceptin was modified at positions 2 or 3 by introduction of β2- or β3-amino acids and additionally in position 1 by replacing Tyr by Dmt (2',6'-dimethyltyrosine), which resulted in obtaining enzymatically stable analogs with mixed opioid receptor affinity profiles. An analog of the sequence Dmt-d-Ala-(R)-β2-1-Nal-Pro-NH2 [Nal=3-(1-naphthyl)-alanine] showed very high activity at the mu and delta receptors in the calcium mobilization functional test but did not cross the artificial membrane imitating the blood-brain barrier. In the in vivo test this analog induced strong antinociceptive effect in the writhing test in mice after intraperitioneal but also oral administration and inhibited diarrhea similarly to loperamide. Therefore, it may become an interesting lead compound in the development of peripherally restricted drugs for the treatment of gastrointestinal disorders.

• Authors: Katarzyna Gach-Janczak, Justyna Piekielna-Ciesielska, Anna Adamska-Bartłomiejczyk, Renata Perlikowska, Rafał Kruszyński, Alicja Kluczyk, Julia Krzywik, Jarosław Sukiennik, Maria Camilla Cerlesi, Girolamo Calo, Andrzej Wasilewski, Marta Zielińska, Anna Janecka
• Journal: Peptides (Peptides) Vol. 95 Pg. 116-123 (Sep 2017) ISSN: 1873-5169 [Electronic] United States
• PMID: 28782637 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Analgesics
• Endorphins
• Opioid Peptides
• Peptidomimetics
• Receptors, Opioid, mu
• morphiceptin

Topics

• Amino Acid Sequence (genetics)
• Analgesics (chemistry, therapeutic use)
• Animals
• Blood-Brain Barrier (drug effects)
• Endorphins (chemistry, genetics, therapeutic use)
• Humans
• Mice
• Opioid Peptides (chemistry, genetics, therapeutic use)
• Pain (drug therapy, genetics)
• Peptidomimetics (chemistry, therapeutic use)
• Receptors, Opioid, mu (chemistry, genetics)