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.

Figure 1

Structure of JNJ-5207852, 1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidine.

Figure 2

(a) Binding of ³H-JNJ-5207852 to rat H₃ receptor. Membranes from rat brain were incubated with increasing concentrations of ³H-JNJ-5207852. Nonspecific binding was determined in the presence of 10 μM histamine. (b) In vitro autoradiography of histamine H₃ receptors in sagittal sections from mouse brain. Sections from wild-type (H₃^+/+, top) and knockout (H₃^−/−, bottom) mice were incubated with 3 nM ³H-JNJ-5207852 for 10 min prior to washing. Cortex (Cx), striatum (Str), hypothalamus (Hyp) and cerebellum (Cer) are indicated by arrows. Bar indicates 1 cm.

Figure 3

Occupancy of H₃ receptors by JNJ-5207852 and thioperamide in the rat striatum 1 h after s.c. adminstration (n=3 animals per dose group). Top, digital image obtained after 1-h acquisition with a β-imager, showing the dose-dependent inhibition of [³H]-R-α-methylhistamine binding by JNJ-5207852 in rat forebrain sections. Bottom, individual values and mean curves illustrating the dose-dependent occupancy of H₃ receptors by JNJ-5207852 (ED₅₀=0.13 mg kg⁻¹) and thioperamide (ED₅₀=2 mg kg⁻¹). Bar indicates 2 cm.

Figure 4

Arousal response to 1 and 10 mg kg⁻¹ (s.c.) of JNJ-5207852 in the rat. Black square: vehicle; black triangle: 1 mg kg⁻¹ JNJ-5207852; white square: 10 mg kg⁻¹ JNJ-15207852. The compound was administered s.c. at t=0 min. Sleep–wake behavior was monitored for two epochs of 30 min prior to and three epochs after dosing, and expressed as average time spent in each of the sleep/waking states. (a) total time awake; (b) SWS; (c) quiet waking; (d) active waking; (e) REM sleep. Data are shown as average±s.e.m. of 3–4 animals. ^*P<0.05, statistically significant from the response in the vehicle-treated animals.

Figure 5

Effect of JNJ-5207852 on amounts of sleep and wakefulness in wild type H₃^+/+ (n=6, left column) and H₃^−/− (n=6, right column) mice. Time (% of total recording time) spent in wakefulness (top), SWS sleep (middle) and SWS delta power (bottom) in 2-h intervals over 24 h of recording. Each animal received an s.c. injection of vehicle or 10 mg kg⁻¹ JNJ-5207852 at light onset. The dark bar on the axis represents the 12-h dark period. In wild-type mice, JNJ-5207852 (10 mg kg⁻¹) significantly increased wakefulness and decreased SWS sleep time and SWS delta power compared to the vehicle condition (^*P<0.05, ^**P<0.01, ^***P<0.001), whereas JNJ-5207852 had no effect on wake or sleep times in H₃^−/− mice.

Figure 6

Effect of JNJ-5207852 on the structure of sleep and wakefulness in wild-type H₃^+/+ (n=6) mice. Data are averaged into 2-h intervals across the 24-h recording following injections of vehicle or 10 mg kg⁻¹ JNJ-5207852 at light onset. The dark bar on the axis represents the 12-h dark period. These data show that the wake-promoting effect of JNJ-5207852 in wild-type mice was due to an increase in the number of wake and sleep bouts (top panels) and a decrease in the average duration of individual wake and SWS bouts (bottom panels) (^*P<0.05, ^**P<0.01, ^***P<0.001).

Figure 7

Effect of JNJ-5207852 on locomotor activity in rats. The animals were observed for 90 min after s.c. administration of 3, 10 or 30 mg kg⁻¹ JNJ-5207852 or 0.75 mg kg⁻¹ D-amphetamine (AMPH). Results are shown as the average±s.e.m. of 6–7 animals. ^*** P<0.001 from vehicle.

Figure 8

Average plasma concentrations of JNJ-5207852 in male and female rats following administration of a single i.p. bolus (10 mg kg⁻¹) or oral (30 mg kg⁻¹) dose of JNJ-5207852. Results are represented as average±s.e.m. of n=4.