Pharmacological profile of SB-357134:: A potent, selective, brain penetrant, and orally active 5-HT6 receptor antagonist

N-(2,5-Dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (SB-357134) potently inhibited [I-125]SB-258585 and [H-3]LSD binding in a HeLa cell line expressing human 5-HT6 receptors (pK(i) = 8.6 and 8.54, respectively). Furthermore, SB-357134 inhibited [125 I]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-HT6 receptor versus 72 other receptors and enzymes. 5-HT-stimulated cyclic AMP (cAMP) accumulation in human 5-HT6 receptors was competitively antagonised by SB-357134 (pA(2) = T63). SB-357134 inhibited ex vivo [125 I]SB-258585 binding in the rat with an ED50 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 It 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 muM. respectively, I 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-HT6 receptor antagonist. (C) 2002 Elsevier Science Inc. All rights reserved.