Characterization of SB-271046: A potent, selective and orally active 5-HT6 receptor antagonist
Article first published online: 29 JAN 2009
2000 British Pharmacological Society
British Journal of Pharmacology
Volume 130, Issue 7, pages 1606–1612, August 2000
How to Cite
Routledge, C., Bromidge, S. M., Moss, S. F., Price, G. W., Hirst, W., Newman, H., Riley, G., Gager, T., Stean, T., Upton, N., Clarke, S. E., Brown, A. M. and Middlemiss, D. N. (2000), Characterization of SB-271046: A potent, selective and orally active 5-HT6 receptor antagonist. British Journal of Pharmacology, 130: 1606–1612. doi: 10.1038/sj.bjp.0703457
- Issue published online: 29 JAN 2009
- Article first published online: 29 JAN 2009
- (Received November 5, 1999, Revised March 30, 2000, Accepted May 4, 2000)
- Human 5-HT6 receptor;
- adenylyl cyclase;
- rat maximal electroshock seizure threshold (MEST) test;
SB-271046, potently displaced [3H]-LSD and [125I]-SB-258585 from human 5-HT6 receptors recombinantly expressed in HeLa cells in vitro (pKi 8.92 and 9.09 respectively). SB-271046 also displaced [125I]-SB-258585 from human caudate putamen and rat and pig striatum membranes (pKi 8.81, 9.02 and 8.55 respectively).
SB-271046 was over 200 fold selective for the 5-HT6 receptor vs 55 other receptors, binding sites and ion channels.
In functional studies on human 5-HT6 receptors SB-271046 competitively antagonized 5-HT-induced stimulation of adenylyl cyclase activity with a pA2 of 8.71.
SB-271046 produced an increase in seizure threshold over a wide-dose range in the rat maximal electroshock seizure threshold (MEST) test, with a minimum effective dose of 0.1 mg kg−1 p.o. and maximum effect at 4 h post-dose. The level of anticonvulsant activity achieved correlated well with the blood concentrations of SB-271046 (EC50 of 0.16 μM) and brain concentrations of 0.01–0.04 μM at Cmax.
These data, together with the observed anticonvulsant activity of other selective 5-HT6 receptor antagonists, SB-258510 (10 mg kg−1, 2–6 h pre-test) and Ro 04-6790 (1–30 mg kg−1, 1 h pre-test), in the rat MEST test, suggest that the anticonvulsant properties of SB-271046 are likely to be mediated by 5-HT6 receptors.
Overall, these studies demonstrate that SB-271046 is a potent and selective 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 function of 5-HT6 receptors.
British Journal of Pharmacology (2000) 130, 1606–1612; doi:10.1038/sj.bjp.0703457