Multifunctional Enkephalin Analogs with a New Biological Profile: MOR/DOR Agonism and KOR Antagonism
| Autor: | Michael Remesic, John M. Streicher, Zhijun Wu, Gabriella Molnar, Victor J. Hruby, Frank Porreca, Yeon Sun Lee, Justin LaVigne, Aleksandra Misicka, Cyf Ramos-Colon, Dagmara Tymecka |
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| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | Biomedicines, Vol 9, Iss 625, p 625 (2021) Biomedicines Volume 9 Issue 6 |
| ISSN: | 2227-9059 |
| Popis: | 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 (GTPγS 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. |
| Databáze: | OpenAIRE |
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