Wake-promoting agents such as modafinil are used in the clinic as adjuncts to antidepressant therapy in order to alleviate lethargy. The wake-promoting action of histamine H-3 receptor antagonists has been evidenced in numerous animal studies. They may therefore be a viable strategy for use as an antidepressant therapy in conjunction with selective serotonin reuptake inhibitors. JNJ-28583867 (2-Methyl-4-(4-methylsulfanylphenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline) is a selective and potent histamine H-3 receptor antagonist (K-i = 10.6 nM) and inhibitor of the serotonin transporter (SERT) (K-i=3.7 nM), with 30-fold selectivity for SERT over the dopamine and norepinephrine transporters. After subcutaneous administration, JNJ-28583867 occupied both the histamine H-3 receptor and the SERT in rat brain at low doses (< 1 mg/kg). JNJ-28583867 blocked imetit-induced drinking (3-10 mg/kg i.p.), confirming in vivo functional activity at the histamine H-3 receptor and also significantly increased cortical extracellular levels of serotonin at doses of 0.3 mg/kg (s.c.) and higher. Smaller increases in cortical extracellular levels of norepinephrine and dopamine were also observed. JNJ-28583867 (3-30 mg/kg p.o.) showed antidepressant-like activity in the mouse tail suspension test. JNJ-28583867 (1-3 mg/kg s.c.) caused a dose-dependent increase in the time spent awake mirrored by a decrease in NREM. Concomitantly, JNJ-28583867 produced a potent su ae-28583867 has good oral bioavailability in the rat (32%), a half-life of 6.9 It and a C-max of 260 ng/ml after 10 mg/kg p.o. In summary, JNJ-28583867 is a combined histamine H-3 receptor antagonist-SERT inhibitor with in vivo efficacy in biochemical and behavioral models of depression and wakefulness. (c) 2007 Elsevier B.V. All rights reserved.
