Bis-Cyclic Guanidine Heterocyclic Peptidomimetics as Opioid Ligands with Mixed μ-, κ- and δ-Opioid Receptor Interactions: A Potential Approach to Novel Analgesics

Int J Mol Sci. 2022 Aug 25;23(17):9623. doi: 10.3390/ijms23179623.

Abstract

The design and development of analgesics with mixed-opioid receptor interactions has been reported to decrease side effects, minimizing respiratory depression and reinforcing properties to generate safer analgesic therapeutics. We synthesized bis-cyclic guanidine heterocyclic peptidomimetics from reduced tripeptides. In vitro screening with radioligand competition binding assays demonstrated variable affinity for the mu-opioid receptor (MOR), delta-opioid receptor (DOR), and kappa-opioid receptor (KOR) across the series, with compound 1968-22 displaying good affinity for all three receptors. Central intracerebroventricular (i.c.v.) administration of 1968-22 produced dose-dependent, opioid receptor-mediated antinociception in the mouse 55 °C warm-water tail-withdrawal assay, and 1968-22 also produced significant antinociception up to 80 min after oral administration (10 mg/kg, p.o.). Compound 1968-22 was detected in the brain 5 min after intravenous administration and was shown to be stable in the blood for at least 30 min. Central administration of 1968-22 did not produce significant respiratory depression, locomotor effects or conditioned place preference or aversion. The data suggest these bis-cyclic guanidine heterocyclic peptidomimetics with multifunctional opioid receptor activity may hold potential as new analgesics with fewer liabilities of use.

Keywords: antinociception; combinatorial chemistry; heterocyclic peptidomimetics; multifunctional opioid agonist; opioid receptors; solid-phase synthesis.

MeSH terms

  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Analgesics, Opioid
  • Animals
  • Guanidine / pharmacology
  • Guanidines / pharmacology
  • Ligands
  • Mice
  • Peptidomimetics* / chemistry
  • Peptidomimetics* / pharmacology
  • Receptors, Opioid
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, kappa / metabolism
  • Receptors, Opioid, mu / metabolism
  • Respiratory Insufficiency*

Substances

  • Analgesics
  • Analgesics, Opioid
  • Guanidines
  • Ligands
  • Peptidomimetics
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Guanidine