A selective small molecule NOP (ORL-1 receptor) partial agonist for the treatment of anxiety

Bioorg Med Chem Lett. 2015 Feb 1;25(3):602-6. doi: 10.1016/j.bmcl.2014.12.015. Epub 2014 Dec 17.

Abstract

Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical δ, μ and κ opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented.

Keywords: Drug discovery; NOP receptor; Nociceptin; Opioid receptor-like receptor-1; Orphanin FQ.

MeSH terms

  • Animals
  • Anxiety / drug therapy
  • Disease Models, Animal
  • Motor Activity / drug effects
  • Nociceptin
  • Nociceptin Receptor
  • Opioid Peptides / chemistry
  • Opioid Peptides / metabolism
  • Protein Binding
  • Rats
  • Receptors, Opioid / agonists*
  • Receptors, Opioid / metabolism
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use
  • Spiro Compounds / chemistry*
  • Spiro Compounds / pharmacology
  • Spiro Compounds / therapeutic use
  • Structure-Activity Relationship

Substances

  • 3-(3-(benzyl-butyl-amino)-2-hydroxypropyl)-8-cyclooctylmethyl-1-(4-fluorophenyl)-1,3,8-triazaspiro(4.5)decan-4-one
  • Opioid Peptides
  • Receptors, Opioid
  • Small Molecule Libraries
  • Spiro Compounds
  • Nociceptin Receptor
  • Oprl protein, rat