The selective 5-HT 1A receptor agonist, NLX-112, exerts anti-dyskinetic effects in MPTP-treated macaques

Parkinsonism Relat Disord. 2020 Sep;78:151-157. doi: 10.1016/j.parkreldis.2020.08.009. Epub 2020 Aug 13.

Abstract

Background: Long-term treatment of Parkinson's disease (PD) with l-DOPA typically leads to development of l-DOPA induced dyskinesia (LID). Amantadine, an NMDA antagonist, attenuates LID, but with limited efficacy and considerable side-effects. NLX-112 (also known as befiradol or F13640), a highly selective and efficacious 5-HT1A receptor agonist, reduced LID when tested in rodent and marmoset models of PD.

Methods: The effects of NLX-112 (0.03, 0.1 and 0.3 mg/kg PO) on established LID evoked by acute challenge with l-DOPA (27.5 ± 3.8 mg/kg PO) were assessed in MPTP-treated cynomolgus macaques. Amantadine (10 mg/kg PO) was tested as a positive control. Plasma exposure of NLX-112 (0.1 mg/kg PO) was determined.

Results: NLX-112 significantly and dose-dependently reduced median LID levels by up to 96% during the first hour post-administration (0.3 mg/kg). Moreover, NLX-112 reduced the duration of 'bad on-time' associated with disabling LID by up to 48% (0.3 mg/kg). In contrast, NLX-112 had negligible impact on the anti-parkinsonian benefit of l-DOPA. NLX-112 exposure peaked at ~50 ng/ml at 30 min post-administration but decreased to ~15 ng/ml at 2h. Amantadine reduced by 42% 'bad on-time' associated with l-DOPA, thereby validating the model.

Conclusion: These data show that, in MPTP-lesioned cynomolgus macaques, NLX-112 exerts robust anti-dyskinetic effects, without reducing the anti-parkinsonian benefit of l-DOPA. These observations complement previous findings and suggest that selective and high efficacy activation of 5-HT1A receptors by NLX-112 may constitute a promising approach to combat LID in PD, providing an alternative for patients in whom amantadine is poorly tolerated or without useful effect.

Keywords: Amantadine; Befiradol; MPTP; Macaques; NLX-112; Parkinson's disease; Serotonin 5-HT(1A) receptors; l-DOPA-induced dyskinesia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amantadine / administration & dosage
  • Amantadine / pharmacology*
  • Animals
  • Disease Models, Animal
  • Dopamine Agents / adverse effects
  • Dopamine Agents / pharmacology*
  • Dyskinesia, Drug-Induced / drug therapy*
  • Dyskinesia, Drug-Induced / etiology
  • Female
  • Levodopa / adverse effects
  • Levodopa / pharmacology*
  • Macaca fascicularis
  • Parkinsonian Disorders / drug therapy*
  • Piperidines / administration & dosage
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Pyridines / administration & dosage
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Serotonin 5-HT1 Receptor Agonists / administration & dosage
  • Serotonin 5-HT1 Receptor Agonists / pharmacokinetics
  • Serotonin 5-HT1 Receptor Agonists / pharmacology*

Substances

  • Dopamine Agents
  • Piperidines
  • Pyridines
  • Serotonin 5-HT1 Receptor Agonists
  • Levodopa
  • Amantadine
  • befiradol