Discovery of cyanoguanidine derivatives as biased μ-opioid receptor agonists

Bioorg Med Chem. 2024 Nov 15:114:117943. doi: 10.1016/j.bmc.2024.117943. Epub 2024 Oct 16.

Abstract

Opioid agonists, including morphine and its derivatives, have historically been utilized in conventional pain relief therapies. However, the morphine-like side effects associated with these compounds have constrained their broader application in clinical environments. Fortunately, novel compounds that selectively activate μ-opioid receptors (MOR) without activating the β-arrestin2 pathway, such as PZM21 and TRV130, demonstrate the potential to mitigate side effects while maintaining analgesic efficacy. In this study, we structurally modified PZM21 to get a series of compounds with a 2-cyanoguanidine scaffold, the majority of which display significant analgesic effects. Notably, Compound I-11 exhibited an analgesic effect comparable to that of morphine and selectively activates μ-opioid receptors while avoiding the activation of the β-arrestin2 pathway. Our work not only introduces a novel biased μ-opioid receptor agonist but also serves as a valuable reference for the further optimization of PZM21.

Keywords: 2-Cyanoguanidine scaffold; Analgesic; Biased μ-opioid receptor agonists; β-Arrestin2.

MeSH terms

  • Analgesics, Opioid* / chemical synthesis
  • Analgesics, Opioid* / chemistry
  • Analgesics, Opioid* / pharmacology
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Guanidines* / chemical synthesis
  • Guanidines* / chemistry
  • Guanidines* / pharmacology
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Molecular Structure
  • Receptors, Opioid, mu* / agonists
  • Receptors, Opioid, mu* / metabolism
  • Structure-Activity Relationship

Substances

  • Receptors, Opioid, mu
  • Guanidines
  • Analgesics, Opioid
  • dicyandiamido