title: SB-656104-A, a novel selective 5-HT7 receptor antagonist, modulates REM sleep in rats.
abstract: 1 (6-((R)-2-[2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl]-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride) (SB-656104-A), a novel 5-hydroxytryptamine (5-HT(7)) receptor antagonist, potently inhibited [(3)H]-SB-269970 binding to the human cloned 5-HT(7(a)) (pK(i) 8.7+/-0.1) and 5-HT(7(b)) (pK(i) 8.5+/-0.2) receptor variants and the rat native receptor (pK(i) 8.8+/-0.2). The compound displayed at least 30-fold selectivity for the human 5-HT(7(a)) receptor versus other human cloned 5-HT receptors apart from the 5-HT(1D) receptor ( approximately 10-fold selective). 2 SB-656104-A antagonised competitively the 5-carboxamidotryptamine (5-CT)-induced accumulation of cyclic AMP in h5-HT(7(a))/HEK293 cells with a pA(2) of 8.5. 3 Following a constant rate iv infusion to steady state in rats, SB-656104 had a blood clearance (CL(b)) of 58+/-6 ml min(-1) kg(-1) and was CNS penetrant with a steady-state brain : blood ratio of 0.9 : 1. Following i.p. administration to rats (10 mg kg(-1)), the compound displayed a t(1/2) of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 micro M, respectively. 4 SB-656104-A produced a significant reversal of the 5-CT-induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5-HT(7) receptor interaction in vivo (ED(50) 2 mg kg(-1)). 5 SB-656104-A, administered to rats at the beginning of the sleep period (CT 0), significantly increased the latency to onset of rapid eye movement (REM) sleep at 30 mg kg(-1) i.p. (+93%) and reduced the total amount of REM sleep at 10 and 30 mg kg(-1) i.p. with no significant effect on the latency to, or amount of, non-REM sleep. SB-269970-A produced qualitatively similar effects in the same study. 6 In summary, SB-656104-A is a novel 5-HT(7) receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5-HT(7) receptors in the modulation of REM sleep.
authors.affiliation: Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park (North), Harlow, Essex. David_R_Thomas@GSK.com
authors.forename: David R
authors.initials: DR
authors.lastname: Thomas
authors.forename: Sergio
authors.initials: S
authors.lastname: Melotto
authors.forename: Mario
authors.initials: M
authors.lastname: Massagrande
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Gribble
authors.forename: Phillip
authors.initials: P
authors.lastname: Jeffrey
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Stevens
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Deeks
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Eddershaw
authors.forename: Susan H
authors.initials: SH
authors.lastname: Fenwick
authors.forename: Graham
authors.initials: G
authors.lastname: Riley
authors.forename: Tania
authors.initials: T
authors.lastname: Stean
authors.forename: Claire M
authors.initials: CM
authors.lastname: Scott
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hill
authors.forename: Derek N
authors.initials: DN
authors.lastname: Middlemiss
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Hagan
authors.forename: Gary W
authors.initials: GW
authors.lastname: Price
authors.forename: Ian T
authors.initials: IT
authors.lastname: Forbes
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004333:Drug Administration Routes; D005786:Gene Expression Regulation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D010636:Phenols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics; D012701:Serotonin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000502:physiology; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012895:Sleep, REM / Q000187:drug effects* / Q000502:physiology*; D014316:Tritium
chemical_list: D010636:Phenols; D011759:Pyrrolidines; D011985:Receptors, Serotonin; C475591:SB-656104-A; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; D014316:Tritium; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C047087:5-carboxamidotryptamine; D000242:Cyclic AMP