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Multifunctional Enkephalin Analogs with a New Biological Profile: MOR/DOR Agonism and KOR Antagonism
- Source :
- Biomedicines, Vol 9, Iss 625, p 625 (2021), Biomedicines, Volume 9, Issue 6
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
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 (GTPĪ³S 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.
- Subjects :
- 0301 basic medicine
Agonist
Enkephalin
QH301-705.5
medicine.drug_class
Medicine (miscellaneous)
(+)-Naloxone
Pharmacology
opioid receptors
Article
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
multifunctional activity
medicine
plasma stability
Biology (General)
IC50
Tetrapeptide
Chemistry
Antagonist
Ligand (biochemistry)
Salvinorin A
030104 developmental biology
template-based alignment modeling
analgesic effects
peptidomimetics
kappa receptor antagonists
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 22279059
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Biomedicines
- Accession number :
- edsair.doi.dedup.....78ae445dd32e36a3c9bd3630575031e6