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Characterization of SB‐271046: A potent, selective and orally active 5‐HT 6 receptor antagonist
Author(s) -
Routledge Carol,
Bromidge Steven M,
Moss Stephen F,
Price Gary W,
Hirst Warren,
Newman Helen,
Riley Graham,
Gager Tracey,
Stean Tania,
Upton Neil,
Clarke Stephen E,
Brown Anthony M,
Middlemiss Derek N
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703457
Subject(s) - receptor , 5 ht receptor , anticonvulsant , chemistry , pharmacology , antagonist , adenylyl cyclase , serotonin , endocrinology , stimulation , medicine , receptor antagonist , biology , biochemistry , epilepsy , neuroscience
SB‐271046, potently displaced [ 3 H]‐LSD and [ 125 I]‐SB‐258585 from human 5‐HT 6 receptors recombinantly expressed in HeLa cells in vitro (p K i 8.92 and 9.09 respectively). SB‐271046 also displaced [ 125 I]‐SB‐258585 from human caudate putamen and rat and pig striatum membranes (p K i 8.81, 9.02 and 8.55 respectively). SB‐271046 was over 200 fold selective for the 5‐HT 6 receptor vs 55 other receptors, binding sites and ion channels. In functional studies on human 5‐HT 6 receptors SB‐271046 competitively antagonized 5‐HT‐induced stimulation of adenylyl cyclase activity with a pA 2 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 (EC 50 of 0.16 μ M ) and brain concentrations of 0.01–0.04 μ M at C max . These data, together with the observed anticonvulsant activity of other selective 5‐HT 6 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‐HT 6 receptors. Overall, these studies demonstrate that SB‐271046 is a potent and selective 5‐HT 6 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‐HT 6 receptors.British Journal of Pharmacology (2000) 130 , 1606–1612; doi: 10.1038/sj.bjp.0703457