Characterization of SB-271046: A potent, selective and orally active 5-HT6receptor antagonist

1 SB-271046, potently displaced [H-3]-LSD and [I-125]-SB-258585 from human 5-HT6 receptors recombinantly expressed in HeLa cells in vitro (pK(i) 8.92 and 9.09 respectively). SB-271046 also displaced [I-125]-SB-258585 from hum an caudate putamen and rat and pig striatum membranes (PKi 8.81, 9.02 and 8 .55 respectively). 2 SB-271046 was over 200 fold selective for the 5-HT6 receptor vs 55 other receptors, binding sites and ion channels. 3 In functional studies on human 5-HT6 receptors SB-271046 competitively an tagonized 5-HT-induced stimulation of adenylyl cyclase activity with a pA(2 ) of 8.71. 4 SB-271046 produced an increase in seizure threshold over a wide-dose rang e in the rat maximal electroshock seizure threshold (MEST) test, with a min imum effective dose of less than or equal to 0.1 mg kg(-1) p.o. and maximum effect at 4 h post-dose. The level of anticonvulsant activity achieved cor related well with the blood concentrations of SB-271046 (EC50 of 0.16 mu M) and brain concentrations of 0.01-0.04 mu M at C-max. 5 These data, together with the observed anticonvulsant activity of other s elective 5-HT6 receptor antagonists, SB-258510 (10 mg kg(-1), 2-6 h pre-tes t) and Ro 04-6790 (1-30 mg kg(-1), 1 h pre-test), in the rat MEST test, sug gest that the anticonvulsant properties of SB-271046 are likely to be media ted by 5-HT6 receptors. 6 Overall, these studies demonstrate that SB-271046 is a potent and selecti ve 5-HT6 receptor antagonist and is orally active in the rat MEST test. SB- 271046 represents a valuable tool for evaluating the in vivo central functi on of 5-HT6 receptors.