Anti-Parkinsonian and anti-dyskinetic profiles of two novel potent and selective nociceptin/orphanin FQ receptor agonists

Br J Pharmacol. 2018 Mar;175(5):782-796. doi: 10.1111/bph.14123. Epub 2018 Jan 31.


Background and purpose: We previously showed that nociceptin/orphanin FQ opioid peptide (NOP) receptor agonists attenuate the expression of levodopa-induced dyskinesia in animal models of Parkinson's disease. We now investigate the efficacy of two novel, potent and chemically distinct NOP receptor agonists, AT-390 and AT-403, to improve Parkinsonian disabilities and attenuate dyskinesia development and expression.

Experimental approach: Binding affinity and functional efficacy of AT-390 and AT-403 at the opioid receptors were determined in radioligand displacement assays and in GTPγS binding assays respectively, conducted in CHO cells. Their anti-Parkinsonian activity was evaluated in 6-hydroxydopamine hemi-lesioned rats whereas the anti-dyskinetic properties were assessed in 6-hydroxydopamine hemi-lesioned rats chronically treated with levodopa. The ability of AT-403 to inhibit the D1 receptor-induced phosphorylation of striatal ERK was investigated.

Key results: AT-390 and AT-403 selectively improved akinesia at low doses and disrupted global motor activity at higher doses. AT-403 palliated dyskinesia expression without causing sedation in a narrow therapeutic window, whereas AT-390 delayed the appearance of abnormal involuntary movements and increased their duration at doses causing sedation. AT-403 did not prevent the priming to levodopa, although it significantly inhibited dyskinesia on the first day of administration. AT-403 reduced the ERK phosphorylation induced by SKF38393 in vitro and by levodopa in vivo.

Conclusions and implications: NOP receptor stimulation can provide significant albeit mild anti-dyskinetic effect at doses not causing sedation. The therapeutic window, however, varies across compounds. AT-403 could be a potent and selective tool to investigate the role of NOP receptors in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / antagonists & inhibitors
  • Acetamides / pharmacology*
  • Acetamides / therapeutic use
  • Animals
  • Antiparkinson Agents / pharmacology*
  • Antiparkinson Agents / therapeutic use
  • Corpus Striatum / metabolism
  • Cricetinae
  • Dyskinesia, Drug-Induced / drug therapy*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Levodopa / antagonists & inhibitors
  • Male
  • Nociceptin Receptor
  • Oxidopamine
  • Phosphorylation / drug effects
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use
  • Radioligand Assay
  • Rats
  • Receptors, Opioid / agonists*


  • Acetamides
  • Antiparkinson Agents
  • Piperidines
  • Receptors, Opioid
  • at-403
  • Levodopa
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
  • Oxidopamine
  • Extracellular Signal-Regulated MAP Kinases
  • Nociceptin Receptor