Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2535597 | European Journal of Pharmacology | 2007 | 12 Pages |
Abstract
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 H3 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-methylsulfanyl-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline) is a selective and potent histamine H3 receptor antagonist (Ki = 10.6 nM) and inhibitor of the serotonin transporter (SERT) (Ki = 3.7 nM), with 30-fold selectivity for SERT over the dopamine and norepinephrine transporters. After subcutaneous administration, JNJ-28583867 occupied both the histamine H3 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 H3 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 suppression of REM sleep from the dose of 1 mg/kg onwards. JNJ-28583867 has good oral bioavailability in the rat (32%), a half-life of 6.9 h and a Cmax of 260 ng/ml after 10 mg/kg p.o. In summary, JNJ-28583867 is a combined histamine H3 receptor antagonist-SERT inhibitor with in vivo efficacy in biochemical and behavioral models of depression and wakefulness.
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Authors
Ann J. Barbier, Leah Aluisio, Brian Lord, Ying Qu, Sandy J. Wilson, Jamin D. Boggs, Pascal Bonaventure, Kirsten Miller, Ian Fraser, Lisa Dvorak, Cindy Pudiak, Christine Dugovic, Jonathan Shelton, Curt Mazur, Michael A. Letavic, Nicholas I. Carruthers,