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.

Effects of Nucleus Basalis Magnocellularis Lesions in Rats on Delayed Matching and Non-Matching to Position Tasks.

The effects of quisqualic acid lesions of the nucleus basalis magnocellularis on short-term memory capacities of the rat have been investigated using the delayed matching and non-matching to position tasks. The lesions do not disrupt performance of either task by pretrained animals, but do disrupt the ability to acquire the non-matching contingency, and to reverse to the non-matching task when trained on the matching task. The unidirectional nature of the reversal deficit has been replicated. The generalized disruption of performance of either task by the muscarinic antagonist scopolamine was comparable in lesioned and control rats. The lesions were associated with extensive loss of acetylcholinesterase staining in the basal forebrain and in the neocortex, and 55% depletions of choline acetyltransferase activity in the neocortex but not in the hippocampus. These observations demonstrate that the cholinergic projection from nucleus basalis to the neocortex is not critical for normal short-term memory, but that lesions involving this system do disrupt specific types of conditional discrimination learning.