Characterization of SB-271046: a potent, selective and orally active 5-HT(6) receptor antagonist.
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 (pK(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 (pK(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 < or =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 microM) and brain concentrations of 0.01-0.04 microM 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.
Routledge
C
C
Department of Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW. Carol_Routledge-1@sbphrd.com
Bromidge
S M
SM
Moss
S F
SF
Price
G W
GW
Hirst
W
W
Newman
H
H
Riley
G
G
Gager
T
T
Stean
T
T
Upton
N
N
Clarke
S E
SE
Brown
A M
AM
Middlemiss
D N
DN
D000262:Adenylyl Cyclases / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D006367:HeLa Cells; D006801:Humans; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012640:Seizures / Q000517:prevention & control; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D014162:Transfection
D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D013449:Sulfonamides; D013876:Thiophenes; C097216:serotonin 6 receptor; D000262:Adenylyl Cyclases; C117443:SB 271046