Pharmacological characterization of JNJ-28583867, a histamine H(3) receptor antagonist and serotonin reuptake inhibitor

Eur J Pharmacol. 2007 Dec 8;576(1-3):43-54. doi: 10.1016/j.ejphar.2007.08.009. Epub 2007 Aug 14.


Wake-promoting agents such as modafinil are used in the clinic as adjuncts to antidepressant therapy in order to alleviate lethargy. The wake-promoting action of histamine H(3) receptor antagonists has been evidenced in numerous animal studies. They may therefore be a viable strategy for use as an antidepressant therapy in conjunction with selective serotonin reuptake inhibitors. JNJ-28583867 (2-Methyl-4-(4-methylsulfanyl-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline) is a selective and potent histamine H(3) receptor antagonist (K(i)=10.6 nM) and inhibitor of the serotonin transporter (SERT) (K(i)=3.7 nM), with 30-fold selectivity for SERT over the dopamine and norepinephrine transporters. After subcutaneous administration, JNJ-28583867 occupied both the histamine H(3) receptor and the SERT in rat brain at low doses (<1 mg/kg). JNJ-28583867 blocked imetit-induced drinking (3-10 mg/kg i.p.), confirming in vivo functional activity at the histamine H(3) receptor and also significantly increased cortical extracellular levels of serotonin at doses of 0.3 mg/kg (s.c.) and higher. Smaller increases in cortical extracellular levels of norepinephrine and dopamine were also observed. JNJ-28583867 (3-30 mg/kg p.o.) showed antidepressant-like activity in the mouse tail suspension test. JNJ-28583867 (1-3 mg/kg s.c.) caused a dose-dependent increase in the time spent awake mirrored by a decrease in NREM. Concomitantly, JNJ-28583867 produced a potent suppression of REM sleep from the dose of 1 mg/kg onwards. JNJ-28583867 has good oral bioavailability in the rat (32%), a half-life of 6.9 h and a C(max) of 260 ng/ml after 10 mg/kg p.o. In summary, JNJ-28583867 is a combined histamine H(3) receptor antagonist-SERT inhibitor with in vivo efficacy in biochemical and behavioral models of depression and wakefulness.

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Dogs
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Histamine Antagonists / pharmacokinetics
  • Histamine Antagonists / pharmacology*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Histamine H3 / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Serotonin Uptake Inhibitors / pharmacokinetics
  • Serotonin Uptake Inhibitors / pharmacology*
  • Tetrahydroisoquinolines / pharmacokinetics
  • Tetrahydroisoquinolines / pharmacology*


  • Dopamine Plasma Membrane Transport Proteins
  • Histamine Antagonists
  • JNJ-28583867
  • Norepinephrine Plasma Membrane Transport Proteins
  • Receptors, Histamine H3
  • SLC6A2 protein, human
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Slc6a4 protein, rat
  • Tetrahydroisoquinolines