| Summary: | 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 <b>LYS744</b> (<b>6</b>, Dmt-DNle-Gly-Phe(<i>p</i>-Cl)-Ppp), a multifunctional ligand with MOR/DOR agonist and KOR antagonist activity (GTPγS assay: IC<sub>50</sub> = 52 nM, I<sub>max</sub> = 122% cf. IC<sub>50</sub> = 59 nM, I<sub>max</sub> = 100% for naloxone) with nanomolar range of binding affinity (<i>K</i><sub>i</sub> = 1.3 nM cf. <i>K</i><sub>i</sub> = 2.4 nM for salvinorin A). Based on its unique biological profile, <b>6</b> 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.
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