Acute wake-promoting actions of JNJ-5207852, a novel, diamine-based H3 antagonist

Br J Pharmacol. 2004 Nov;143(5):649-61. doi: 10.1038/sj.bjp.0705964. Epub 2004 Oct 4.


1 1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidine (JNJ-5207852) is a novel, non-imidazole histamine H3 receptor antagonist, with high affinity at the rat (pKi=8.9) and human (pKi=9.24) H3 receptor. JNJ-5207852 is selective for the H3 receptor, with negligible binding to other receptors, transporters and ion channels at 1 microm. 2 JNJ-5207852 readily penetrates the brain tissue after subcutaneous (s.c.) administration, as determined by ex vivo autoradiography (ED50 of 0.13 mg kg(-1) in mice). In vitro autoradiography with 3H-JNJ-5207852 in mouse brain slices shows a binding pattern identical to that of 3H-R-alpha-methylhistamine, with high specific binding in the cortex, striatum and hypothalamus. No specific binding of 3H-JNJ-5207852 was observed in brains of H3 receptor knockout mice. 3 In mice and rats, JNJ-5207852 (1-10 mg kg(-1) s.c.) increases time spent awake and decreases REM sleep and slow-wave sleep, but fails to have an effect on wakefulness or sleep in H3 receptor knockout mice. No rebound hypersomnolence, as measured by slow-wave delta power, is observed. The wake-promoting effects of this H3 receptor antagonist are not associated with hypermotility. 4 A 4-week daily treatment of mice with JNJ-5207852 (10 mg kg(-1) i.p.) did not lead to a change in body weight, possibly due to the compound being a neutral antagonist at the H3 receptor. 5 JNJ-5207852 is extensively absorbed after oral administration and reaches high brain levels. 6 The data indicate that JNJ-5207852 is a novel, potent and selective H3 antagonist with good in vitro and in vivo efficacy, and confirm the wake-promoting effects of H3 receptor antagonists.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Animals
  • Autoradiography
  • Body Temperature / drug effects
  • Body Weight / drug effects
  • Cyclic AMP / metabolism
  • Electrodes
  • Electroencephalography / drug effects
  • Electromyography / drug effects
  • Histamine Antagonists / administration & dosage
  • Histamine Antagonists / pharmacokinetics
  • Histamine Antagonists / pharmacology*
  • Humans
  • Injections, Intravenous
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Obese
  • Motor Activity / drug effects
  • Piperidines / administration & dosage
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Polysomnography
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Histamine H3 / drug effects*
  • Receptors, Histamine H3 / genetics
  • Sleep / drug effects
  • Transducers
  • Wakefulness / drug effects*


  • 1-(4-(3-piperidin-1-ylpropoxy)benzyl)piperidine
  • Histamine Antagonists
  • Piperidines
  • Receptors, Histamine H3
  • Cyclic AMP