Acute wake-promoting actions of JNJ-5207852, a novel, diamine-based H3 antagonist.
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.
Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.
A J
AJ
Barbier
C
C
Berridge
C
C
Dugovic
A D
AD
Laposky
S J
SJ
Wilson
J
J
Boggs
L
L
Aluisio
B
B
Lord
C
C
Mazur
C M
CM
Pudiak
X
X
Langlois
W
W
Xiao
R
R
Apodaca
N I
NI
Carruthers
T W
TW
Lovenberg
D000284:Administration, Oral; D000818:Animals; D001345:Autoradiography; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004566:Electrodes; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography / Q000187:drug effects; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D017286:Polysomnography; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000235:genetics; D012890:Sleep / Q000187:drug effects; D014159:Transducers; D014851:Wakefulness / Q000187:drug effects*
C477200:1-(4-(3-piperidin-1-ylpropoxy)benzyl)piperidine; D006633:Histamine Antagonists; D010880:Piperidines; D018100:Receptors, Histamine H3; D000242:Cyclic AMP