JNJ-18038683

JNJ-18038683 is a 5-Hydroxytryptamine Type 7 (5-HT₇) receptor antagonist, with pK_is of 8.19, 8.20 for rat and human 5-HT₇ in HEK293 cells, respectively. IC50 & Target: pKi: 8.19 (rat 5-HT₇ receptor), 8.20 (human 5-HT₇ receptor)^[1]. In Vitro: JNJ-18038683 displaced, with high affinity, specific [³H]5-CT binding sites from rat and human 5-HT₇ receptor express in HEK293 cells (pK_i=8.19±0.02 and 8.20±0.01, respectively). Similar values are obtained on the native 5-HT₇ in membranes from rat thalamus (pK_i=8.50±0.20). Hill slope values are close to unity, suggesting one-site competitive binding. Antagonist potency of JNJ-18038683 is determined by the measurement of adenylate cyclase activity in HEK293 cells expressing the human or rat 5-HT₇ receptor. 5-HT stimulates adenylyl cyclase activity in rat and human 5-HT₇/HEK293 cells with a pEC₅₀ of 8.09 and 8.12, respectively. JNJ-18038683 produces a concentration-dependent decrease of 5-HT (100 nM)-stimulated adenylyl cyclase. The pK_B values determined for JNJ-18038683 are in good agreement with the corresponding K_i values determined from [³H]5-CT binding studies^[1]. In Vivo: JNJ-18038683 dose-dependently suppresses REM sleep mainly during the first 4 h after the treatment. The duration of REM sleep is significantly decreased from the dose of 1 mg/kg onward (P<0.05) during the first 4 h after oral administration. Concomitantly, the REM sleep latency tends to be prolonged in a dose-related manner with a significant increase in REM latency occurring only at the highest dose tested (10 mg/kg; P<0.05). These alterations in REM sleep seem to be state-specific. A separate study is conducted to determine whether repeated administration of JNJ-18038683 for 7 days would result in an adaptation of the EEG sleep response in particular on REM sleep in rats during the course of the treatment and after its discontinuation. JNJ-18038683 is administered for 7 consecutive days (1 mg/kg s.c. per day) at 2 h into the light phase. On the first day of treatment, JNJ-18038683 produces a significant decrease in the time spent in REM sleep during the first 8 h after the injection and a prolongation of the REM sleep latency. The REM sleep latency is increased during the 7-day repeated treatment and is normalized on the first recovery day after cessation of treatment. The significant decrease in REM sleep time is maintained during the 7-day repeated treatment, with a rebound occurring on the first recovery day after treatment discontinuation. The NREM sleep latency and the total NREM sleep time are not affected during the entire treatment^[1].