Pharmacological profile of SB-357134: a potent, selective, brain penetrant, and orally active 5-HT(6) receptor antagonist.

Abstract

N-(2,5-Dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (SB-357134) potently inhibited [125I]SB-258585 and [3H]LSD binding in a HeLa cell line expressing human 5-HT(6) receptors (pK(i)=8.6 and 8.54, respectively). Furthermore, SB-357134 inhibited [125I]SB-258585 binding in human caudate--putamen and in rat and pig striatum membranes (pK(i)=8.82, 8.44, and 8.61, respectively). SB-357134 displayed over 200-fold selectivity for the 5-HT(6) receptor versus 72 other receptors and enzymes. 5-HT-stimulated cyclic AMP (cAMP) accumulation in human 5-HT(6) receptors was competitively antagonised by SB-357134 (pA(2)=7.63). SB-357134 inhibited ex vivo [125I]SB-258585 binding in the rat with an ED(50) of 4.9 +/- 1.3 mg/kg po, 4 h postdose. In the rat maximal electroshock seizure threshold (MEST) test, SB-357134 produced a potent and dose-dependent increase in seizure threshold, with a minimum effective dose of 0.1 mg/kg po. At 10 mg/kg po, maximum activity occurred between 4 and 6 h postdose. Good exposure was observed with SB-357134 at 10 mg/kg po, reaching maximal blood and brain concentrations of 4.3 +/- 0.2 and 1.3 +/- 0.06 microM, respectively, 1 h postdose. In addition, SB-357134 (10 mg/kg po) enhanced memory and learning following chronic administration (twice a day for 7 days) in the rat water maze. Overall, these studies demonstrate that SB-357134 is a potent, selective, brain penetrant, and orally active 5-HT(6) receptor antagonist.

• Authors: Tania O Stean, Warren D Hirst, David R Thomas, Gary W Price, Derek Rogers, Graham Riley, Steven M Bromidge, Halina T Serafinowska, Douglas R Smith, Sarah Bartlett, Nigel Deeks, Mark Duxon, Neil Upton
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 71 Issue 4 Pg. 645-54 (Apr 2002) ISSN: 0091-3057 [Print] United States
• PMID: 11888556 (Publication Type: Journal Article)

Chemical References

• N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide
• Piperazines
• Receptors, Serotonin
• Recombinant Proteins
• Serotonin Antagonists
• Sulfonamides
• serotonin 6 receptor
• Cyclic AMP

Topics

• Algorithms
• Animals
• Brain (metabolism)
• Brain Chemistry (drug effects)
• Cognition (drug effects)
• Cyclic AMP (metabolism)
• Electroshock
• Exploratory Behavior (drug effects)
• Humans
• Male
• Maze Learning (drug effects)
• Membranes (drug effects, metabolism)
• Piperazines (metabolism, pharmacology)
• Radioligand Assay
• Rats
• Rats, Sprague-Dawley
• Receptors, Serotonin (drug effects, metabolism)
• Recombinant Proteins (drug effects)
• Seizures (prevention & control)
• Serotonin Antagonists (metabolism, pharmacology)
• Sulfonamides (metabolism, pharmacology)
• Swine