Characterisation of the pharmacodynamic effects of the P2X7 receptor antagonist JNJ-54175446 using an oral dexamphetamine challenge model in healthy males in a randomised, double-blind, placebo-controlled, multiple ascending dose trial

J Psychopharmacol. 2020 Sep;34(9):1030-1042. doi: 10.1177/0269881120914206. Epub 2020 Apr 4.


Background: This is the first report of the pharmacodynamic (PD) effects of the selective, potent and brain-penetrant P2X7 receptor (P2X7R) antagonist JNJ-54175446. Activation of the P2X7R, an adenosine triphosphate-gated ion channel, leads to the production of pro-inflammatory cytokines, which have been linked to neuroinflammation and play a role in the pathogenesis of mood disorders. Previous clinical studies with JNJ-54175446 demonstrated peripheral target engagement of JNJ-54175446 by assessing ex vivo lipopolysaccharide (LPS)-stimulated cytokine production. Blood-brain barrier penetration and a clear dose-receptor occupancy relationship was demonstrated using positron emission tomography.

Aims: The objectives of this double-blind, placebo-controlled, translational study were to assess the safety and tolerability of administering multiple doses of JNJ-54175446 and to explore its PD effects using a dexamphetamine challenge.

Methods: Subjects (N = 64) were randomised to either JNJ-54175446 (50-450 mg; n = 48) or placebo (n = 16) and underwent a baseline oral 20 mg dexamphetamine challenge followed by 11 consecutive days q.d. dosing with JNJ-54175446/placebo and a randomised crossover dexamphetamine/placebo challenge.

Results: At all doses tested, JNJ-54175446 was well tolerated and suppressed the ex vivo LPS-induced release of cytokines. At doses ⩾100 mg, JNJ-54175446 attenuated dexamphetamine-induced increases in locomotion and enhanced the mood-elevating effects of dexamphetamine, suggesting that a dose that is approximately twice as high is needed to obtain a central PD response compared to the dose needed for maximum peripheral occupancy.

Conclusion: Overall, the observed pharmacological profile of JNJ-54175446 in the dexamphetamine challenge paradigm is compatible with a potential mood-modulating effect.

Keywords: P2X7; inflammation; major depressive disorder.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / pharmacology*
  • Depressive Disorder, Major / drug therapy
  • Dextroamphetamine / administration & dosage
  • Dextroamphetamine / pharmacology*
  • Double-Blind Method
  • Electroencephalography
  • Humans
  • Inflammation / drug therapy
  • Male
  • Purinergic P2X Receptor Antagonists / administration & dosage
  • Purinergic P2X Receptor Antagonists / adverse effects
  • Purinergic P2X Receptor Antagonists / pharmacokinetics
  • Purinergic P2X Receptor Antagonists / pharmacology*
  • Pyridines / administration & dosage
  • Pyridines / adverse effects
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Translational Research, Biomedical
  • Triazoles / administration & dosage
  • Triazoles / adverse effects
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology*
  • Young Adult


  • Central Nervous System Stimulants
  • Purinergic P2X Receptor Antagonists
  • Pyridines
  • Triazoles
  • JNJ-54175446
  • Dextroamphetamine