• Cyclic biphalin analogues with a novel linker lead to potent agonist activities at mu, delta, and kappa opioid receptors

      Remesic, Michael; Macedonio, Giorgia; Mollica, Adriano; Porreca, Frank; Hruby, Victor; Lee, Yeon Sun; Univ Arizona, Dept Chem & Biochem; Univ Arizona, Dept Pharmacol (PERGAMON-ELSEVIER SCIENCE LTD, 2018-07-23)
      In an effort to improve biphalin's potency and efficacy at the mu-( MOR) and delta-opioid receptors (DOR), a series of cyclic biphalin analogues 1-5 with a cystamine or piperazine linker at the C-terminus were designed and synthesized by solution phase synthesis using Boc-chemistry. Interestingly, all of the analogues showed balanced opioid agonist activities at all opioid receptor subtypes due to enhanced.-opioid receptor (KOR) activity. Our results indicate that C-terminal flexible linkers play an important role in KOR activity compared to that of the other cyclic biphalin analogues with a hydrazine linker. Among them, analogue 5 is a potent (Ki= 0.27, 0.46, and 0.87 nM; EC50= 3.47, 1.45, and 13.5 nM at MOR, DOR, and KOR, respectively) opioid agonist with high efficacy. Based on the high potency and efficacy at the three opioid receptor subtypes, the ligand is expected to have a potential synergistic effect on relieving pain and further studies including in vivo tests are worthwhile.
    • 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.