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 H-3 receptor antagonist, with high affinity at the rat (pK(i) = 8.9) and human (pK(i) = 9.24) H-3 receptor. JNJ-5207852 is selective for the H3 receptor, with negligible binding to other receptors, transporters and ion channels at 1 muM. 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 H-3-JNJ-5207852 in mouse brain slices shows a binding pattern identical to that of H-3-R-alpha-methylhistamine, with high specific binding in the cortex, striatum and hypothalamus. No specific binding of H-3-JNJ-5207852 was observed in brains of H-3 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 H-3 receptor knockout mice. No rebound hypersomnolence, as measured by slow-wave delta power, is observed. The wake-promoting effects of this H-3 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 H-3 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 H-3 antagonist with good in vitro and in vivo efficacy, and confirm the wake-promoting effects of H-3 receptor antagonists.