Memories are Made of This (Perhaps): A Review of Serotonin 5-HT6 Receptor Ligands and Their Biological Functions

Abstract

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.

A Null Mutation of the Serotonin 6 Receptor Alters Acute Responses to Ethanol

“…Pretreatment with a 5-HT 6 R antagonist also improved rat performance of an attentional set-shifting task, a rodent analog of the Wisconsin card sorting test, a commonly used assay of cognitive-guided sorting (Hatcher et al, 2005). However, other investigators have been unable to demonstrate 5-HT 6 R-induced enhancements of cognitive function (Russell and Dias, 2002;Lindner et al, 2003). In three different cohorts, we were unable to demonstrate phenotypic differences in either Morris water maze acquisition or probe trial performance.…”

“…Other studies have implicated Rs in the modulation of cognitive processes (Russell and Dias, 2002). However, studies of the roles of 5-HT 6 Rs in these and other behavioral processes have produced conflicting results.…”

“…Thus, the expression pattern and pharmacological properties of Rs indicate that they may contribute to serotonergic modulation of clinically relevant neuropsychological processes and psychopharmacological responses. Administration of 5-HT 6 R antagonists and antisense oligonucleotides have been reported to produce several behavioral effects in rodents, including feeding suppression (Svartengren et al, 2004), yawning and stretching (Bourson et al, 1995;Sleight et al, 1996;Sleight et al, 1998;Bentley et al, 1999), decreased anxiety-related behaviors (Hamon et al, 1999), and improved performance in learning and memory tasks (Meneses, 2001;Rogers and Hagan, 2001;Woolley et al, 2001;Russell and Dias, 2002;Lindner et al, 2003;Riemer et al, 2003).…”

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

“…Ro046790 enhanced nonspatial working memory in an object recognition task (ORT) (Woolley et al, 2003), increased consolidation in an autoshaping task, and reversed scopolamine-induced deficits in both an autoshaping and a passive avoidance task (Bos et al, 2001;Meneses, 2001). However, some of these effects in the autoshaping and Morris water maze task could not be replicated (Lindner et al, 2003;Russell and Dias, 2002). Although the reason is not known, poor drug properties, such as a low affinity for the 5-HT 6 receptor and a low penetration of the blood-brain barrier, may contribute to a higher variability in behavioral findings with both compounds.…”

“…Recently, 5HT 6 receptor antagonists with improved affinity and selectivity have been developed that demonstrate better penetration into the central nervous system (Russell and Dias, 2002). One of these drugs is Ro4368554, which possesses a blood-brain penetration of 80-110% (against 1 and 10% for Ro046790 and SB271046, respectively).…”