title: Pharmacological profile of SB-357134: a potent, selective, brain penetrant, and orally active 5-HT(6) receptor antagonist.
abstract: N-(2,5-Dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (SB-357134) potently inhibited [125I]SB-258585 and [3H]LSD binding in a HeLa cell line expressing human 5-HT(6) receptors (pK(i)=8.6 and 8.54, respectively). Furthermore, SB-357134 inhibited [125I]SB-258585 binding in human caudate--putamen and in rat and pig striatum membranes (pK(i)=8.82, 8.44, and 8.61, respectively). SB-357134 displayed over 200-fold selectivity for the 5-HT(6) receptor versus 72 other receptors and enzymes. 5-HT-stimulated cyclic AMP (cAMP) accumulation in human 5-HT(6) receptors was competitively antagonised by SB-357134 (pA(2)=7.63). SB-357134 inhibited ex vivo [125I]SB-258585 binding in the rat with an ED(50) of 4.9 +/- 1.3 mg/kg po, 4 h postdose. In the rat maximal electroshock seizure threshold (MEST) test, SB-357134 produced a potent and dose-dependent increase in seizure threshold, with a minimum effective dose of 0.1 mg/kg po. At 10 mg/kg po, maximum activity occurred between 4 and 6 h postdose. Good exposure was observed with SB-357134 at 10 mg/kg po, reaching maximal blood and brain concentrations of 4.3 +/- 0.2 and 1.3 +/- 0.06 microM, respectively, 1 h postdose. In addition, SB-357134 (10 mg/kg po) enhanced memory and learning following chronic administration (twice a day for 7 days) in the rat water maze. Overall, these studies demonstrate that SB-357134 is a potent, selective, brain penetrant, and orally active 5-HT(6) receptor antagonist.
authors.affiliation: Neurology-CEDD, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Essex CM19 5AW, Harlow, UK. tania_stean-1@gsk.com
authors.forename: Tania O
authors.initials: TO
authors.lastname: Stean
authors.forename: Warren D
authors.initials: WD
authors.lastname: Hirst
authors.forename: David R
authors.initials: DR
authors.lastname: Thomas
authors.forename: Gary W
authors.initials: GW
authors.lastname: Price
authors.forename: Derek
authors.initials: D
authors.lastname: Rogers
authors.forename: Graham
authors.initials: G
authors.lastname: Riley
authors.forename: Steven M
authors.initials: SM
authors.lastname: Bromidge
authors.forename: Halina T
authors.initials: HT
authors.lastname: Serafinowska
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Smith
authors.forename: Sarah
authors.initials: S
authors.lastname: Bartlett
authors.forename: Nigel
authors.initials: N
authors.lastname: Deeks
authors.forename: Mark
authors.initials: M
authors.lastname: Duxon
authors.forename: Neil
authors.initials: N
authors.lastname: Upton
mesh_terms: D000465:Algorithms; D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004597:Electroshock; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000187:drug effects; D012640:Seizures / Q000517:prevention & control; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*; D013552:Swine; D000096926:Benzenesulfonamides
chemical_list: D000242:Cyclic AMP; D010879:Piperazines; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D013449:Sulfonamides; C422502:N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide; D000096926:Benzenesulfonamides; C097216:serotonin 6 receptor