A number of evidence indicate that the serotonin (5-hydroxytryptamine, 5-HT) system participates in memory formation. Additionally, recent reviews provide further support to the notion that 5-HT1 to 5-HT4 and 5-HT6 and 5-HT7 receptors may be useful targets for cognitive dysfunctions research.

In this article, we will introduce a potent 5-HT6 receptor antagonist, SB-357134.
In vitro, SB-357134 (0.1, 0.3, 1, and 3 μM) concentration-dependently inhibits the 5-HT-mediated increased level of cAMP.  Besides, it dose-dependently inhibits the specific [¹²⁵I]SB-258585 binding.

In the rat MEST model, SB-357134 (0.03–30 mg/kg; 0-24 h; p.o.; single dose) produces a potent and dose-related anticonvulsant effect in the SD rats. It exhibits a minimum significantly effective dose of 0.1 mg/kg. At 10 mg/kg, SB-357134 shows a rapid onset of action, significantly increasing the seizure threshold from a control value of 21.7 to 26.7 mA at 1 h post-dose. Furthermore, at the dosage of 30 mg/kg, it shows an increased seizure threshold of up to 123±12%. The Observed Peak activity within 4–6 h post-dose. With the exception of an unexplained loss of activity at 12 h, it had a long duration of action of 21 h in this model.

SB-357134 enhances memory and learning and increases seizure threshold in rats.

In the Water maze assay, Acute administration of SB-357134 ( p.o.;10 mg/kg) produced no significant effects on latency to find the platform. However, Chronic administration of SB-357134 (10 mg/kg; p.o.; twice daily; 7 days) significantly shortens path length compared to vehicle and acute administration of SB-357134.

SB-357134 improves memory formation in an auto-shaping learning task. Additionally, Acute administration of SB-357134, at 1, 3, 10, and 30 mg/kg, produces conditioned responses (CR%) inverted-U curve, eliciting the latter dose 7-fold increase relative to the saline group. SB-357134 (10 mg/kg; 7 days)  elicits the most significant CR% increments. A Post hoc Tukey test shows: acute administration of SB-357134, at either 3 or 10 mg/kg, antagonizes scopolamine and dizocilpine effects.

In conclusion, SB-357134 is a potent, selective, brain-penetrant, and orally active 5-HT6 receptor antagonist. SB-357134 has the potential for seizure research.

Reference:

[1] Stean TO, et al. Pharmacol Biochem Behav. 2002 Apr;71(4):645-54.

[2] Georgina Perez-García, et al. Pharmacol Biochem Behav. 2005 Jul;81(3):673-82.