• Multifunctional enkephalin analogs with a new biological profile: Mor/dor agonism and kor antagonism

      Lee, Y.S.; Remesic, M.; Ramos-Colon, C.; Wu, Z.; Lavigne, J.; Molnar, G.; Tymecka, D.; Misicka, A.; Streicher, J.M.; Hruby, V.J.; et al. (MDPI AG, 2021)
      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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.