Abstract
In our previous studies, we developed a series of mixed MOR/DOR agonists that are enkephalin-like tetrapeptide analogs with an N-phenyl-N-piperidin-4-ylpropionamide (Ppp) moiety at the C-terminus. Further SAR study on the analogs, initiated by the findings from off-target screening, resulted in the discovery of LYS744 (6, Dmt-DNle-Gly-Phe(p-Cl)-Ppp), a multifunctional ligand with MOR/DOR agonist and KOR antagonist activity (GTPS assay: IC50 = 52 nM, Imax = 122% cf. IC50 = 59 nM, Imax = 100% for naloxone) with nanomolar range of binding affinity (Ki = 1.3 nM cf.Ki = 2.4 nM for salvinorin A). Based on its unique biological profile, 6 is considered to possess high therapeutic potential for the treatment of chronic pain by modulating pathological KOR activation while retaining analgesic efficacy attributed to its MOR/DOR agonist activity.
Original language | English (US) |
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Article number | 625 |
Journal | Biomedicines |
Volume | 9 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2021 |
Keywords
- Analgesic effects
- Kappa receptor antagonists
- Multifunctional activity
- Opioid receptors
- Peptidomimetics
- Plasma stability
- Template-based alignment modeling
ASJC Scopus subject areas
- Medicine (miscellaneous)
- Biochemistry, Genetics and Molecular Biology(all)