title: Pharmacological characterization of JNJ-28583867, a histamine H(3) receptor antagonist and serotonin reuptake inhibitor.
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 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-methylsulfanyl-phenyl)-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 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 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Barbier
authors.forename: Leah
authors.initials: L
authors.lastname: Aluisio
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.forename: Ying
authors.initials: Y
authors.lastname: Qu
authors.forename: Sandy J
authors.initials: SJ
authors.lastname: Wilson
authors.forename: Jamin D
authors.initials: JD
authors.lastname: Boggs
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.forename: Kirsten
authors.initials: K
authors.lastname: Miller
authors.forename: Ian
authors.initials: I
authors.lastname: Fraser
authors.forename: Lisa
authors.initials: L
authors.lastname: Dvorak
authors.forename: Cindy
authors.initials: C
authors.lastname: Pudiak
authors.forename: Christine
authors.initials: C
authors.lastname: Dugovic
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shelton
authors.forename: Curt
authors.initials: C
authors.lastname: Mazur
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D006633:Histamine Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D006633:Histamine Antagonists; D050484:Norepinephrine Plasma Membrane Transport Proteins; D018100:Receptors, Histamine H3; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D044005:Tetrahydroisoquinolines; C527034:JNJ-28583867; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human; C493232:Slc6a4 protein, rat