The possible role of
5-HT(6) receptor antagonists in the treatment of learning and
memory disorders has stimulated significant recent work in this area. The first selective antagonists of this receptor were identified by Roche (
Ro 04-6790 and
Ro 63-0563) and SmithKline Beecham (SB-271046), although they only had poor to modest brain penetration, respectively. Recently, several structurally different series of selective antagonists have been reported. Glennon s group and Merck Sharp & Dohme have discovered N,N-dimethyl-1-benzenesulfonyl-5-methoxytrypt
amine as a reasonably selective, high affinity antagonist, while Allelix have gone on to find that a 6-bicyclopiperazinyl-1-naphthylsulfonylindole had improved affinity and selectivity. Roche have reported subsequently on more lipophilic analogs of
Ro 04-6790 that appear to penetrate the brain better. Reversing the
sulfonamide linkage of
SB-271046 led to a new series of compounds, producing
SB-357134, which also had increased CNS penetration. A series of selective partial agonists containing a 4-piperazinylquinoline system has also been described. Recent studies in the Morris water maze with both
Ro 04-6790 and
SB-271046 have concluded that
5-HT(6) receptor antagonists improved retention performance, although these results are open to interpretation. Other behavioural studies have also implicated a role for 5-HT(6) in cognition enhancement and this has been supported by in vivo microdialysis studies that showed
SB-271046 produced an increase in extracellular
glutamate levels in the frontal cortex. However, we have been unable to replicate these effects with either
SB-271046 or
Ro 04-6790, and clearly further work is required before we can be certain of the functional role of this receptor.