The possible role of 5-HT6 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. Glennons group and Merck Sharp & Dohme have discovered N,N-dimethyl-1- benzenesulfonyl-5-methoxytryptamine 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-HT6 receptor antagonists improved retention performance, although these results are open to interpretation. Other behavioural studies have also implicated a role for 5-HT6 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.
Merck Sharp&DohmeResearch Laboratories, Neuroscience Research Centre, Terlings Park,Eastwick Road, Harlow, Essex CM20 2QR, UK