SB-399885 is a potent, selective 5-HT 6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models

Abstract

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 p K i values 9.11 ± 0.03 and 9.02 ± 0.05, respectively and is a potent competitive antagonist (p A 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 [ 125I]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.