SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models.
SB-399885 (N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide) has high affinity for human recombinant and native 5-HT(6) receptors, with pK(i) values 9.11+/-0.03 and 9.02+/-0.05, respectively and is a potent competitive antagonist (pA(2) 7.85+/-0.04). It displays over 200-fold selectivity for the 5-HT(6) receptor over all other receptors, ion channels and enzymes tested to date. SB-399885 inhibited ex vivo [(125)I]SB-258585 (4-Iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulfonamide) binding with an ED(50) of 2.0+/-0.24 mg/kg p.o. in rats. It had a minimum effective dose of 1 mg/kg p.o. in a rat maximal electroshock seizure threshold test and a long duration of action, overall demonstrating an excellent pharmacokinetic-pharmacodynamic correlation. Repeated administration of this agent (10 mg/kg p.o., b.i.d. for 7 days) significantly reversed a scopolamine-induced deficit (0.5 mg/kg i.p.) in a rat novel object recognition paradigm. Moreover, in aged rats (22 months old) SB-399885 (10 mg/kg p.o., b.i.d. for 7 days) fully reversed the age-dependent deficit in water maze spatial learning compared to vehicle-treated age-matched controls and significantly improved recall of the task measured by increases in the searching of the target quadrant on post-training days 1, 3 and 7. In vivo microdialysis in the rat medial prefrontal cortex demonstrated that acute SB-399885 (10 mg/kg p.o.) significantly increased extracellular acetylcholine levels. These data demonstrate that SB-399885 is a potent, selective, brain penetrant, orally active 5-HT(6) receptor antagonist with cognitive enhancing properties that are likely to be mediated by enhancements of cholinergic function. These studies provide further support for the potential therapeutic utility of 5-HT(6) receptor antagonists in disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.
Hirst
Warren D
WD
Neurology & GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, CM19 5AW, UK.
Stean
Tania O
TO
Rogers
Derek C
DC
Sunter
David
D
Pugh
Pippa
P
Moss
Stephen F
SF
Bromidge
Steven M
SM
Riley
Graham
G
Smith
Douglas R
DR
Bartlett
Sarah
S
Heidbreder
Christian A
CA
Atkins
Alan R
AR
Lacroix
Laurent P
LP
Dawson
Lee A
LA
Foley
Andrew G
AG
Regan
Ciaran M
CM
Upton
Neil
N
D000109:Acetylcholine / Q000378:metabolism; D000375:Aging / Q000523:psychology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003071:Cognition / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D006367:HeLa Cells; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D017551:Microdialysis; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D021641:Recognition, Psychology / Q000187:drug effects*; D012640:Seizures / Q000517:prevention & control; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology*
D010879:Piperazines; D011985:Receptors, Serotonin; C503990:SB 399885; D012702:Serotonin Antagonists; D013449:Sulfonamides; C097216:serotonin 6 receptor; D000242:Cyclic AMP; D000109:Acetylcholine