The search for opioid analgesics with limited tolerance liability

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2020-08, Vol.130, p.170331-170331, Article 170331
• Main Authors: Wtorek, Karol, Piekielna-Ciesielska, Justyna, Janecki, Tomasz, Janecka, Anna
• Format: Article
• Language: English
• Subjects: Antinociceptive activity; G protein-coupled receptors; Mixed-efficacy opioid ligands; Peptidomimetics; Tolerance
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2020.170331

•Analgesic activity of morphine is associated with serious side effects.•One of these side effects is the development of tolerance.•Tolerance necessitates dose escalation resulting in a clinical vicious circle.•Analogs with MOR agonist/DOR antagonist profile attenuate tolerance development.•Peptides and peptidomimetics with such opioid receptor profile are described. Reducing the well-known side effects of opioids prescribed to treat chronic pain remains unresolved, despite extensive research in this field. Among several options to tackle this problem the synthesis of multifunctional compounds containing hybridized structures gained a lot of interest. Recently, extensively investigated are combinations of opioid agonist and antagonist pharmacophores embodied in a single molecule. To this end, agonism at the μ opioid receptor (MOR) with simultaneous antagonism at the δ opioid receptor (DOR) emerged as a promising avenue to obtaining novel analogs devoid of serious adverse effects associated with morphine-based analgesics. In this review we covered up-to-date research on the synthesis of peptide-based ligands with MOR agonist/DOR antagonist profile.