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

Abstract

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.

• Authors: A J Barbier, C Berridge, C Dugovic, A D Laposky, S J Wilson, J Boggs, L Aluisio, B Lord, C Mazur, C M Pudiak, X Langlois, W Xiao, R Apodaca, N I Carruthers, T W Lovenberg
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 143 Issue 5 Pg. 649-61 (Nov 2004) ISSN: 0007-1188 [Print] England
• PMID: 15466448 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

• 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, pharmacokinetics, pharmacology)
• Humans
• Injections, Intravenous
• Male
• Mice
• Mice, Knockout
• Mice, Obese
• Motor Activity (drug effects)
• Piperidines (administration & dosage, pharmacokinetics, pharmacology)
• Polysomnography
• Rats
• Rats, Sprague-Dawley
• Receptors, Histamine H3 (drug effects, genetics)
• Sleep (drug effects)
• Transducers
• Wakefulness (drug effects)