Characterization of SB-271046: a potent, selective and orally active 5-HT(6) receptor antagonist.

Abstract

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.

• Authors: C Routledge, S M Bromidge, S F Moss, G W Price, W Hirst, H Newman, G Riley, T Gager, T Stean, N Upton, S E Clarke, A M Brown, D N Middlemiss
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 130 Issue 7 Pg. 1606-12 (Aug 2000) ISSN: 0007-1188 [Print] England
• PMID: 10928964 (Publication Type: Journal Article)

Chemical References

• Receptors, Serotonin
• Recombinant Proteins
• Serotonin Antagonists
• Sulfonamides
• Thiophenes
• serotonin 6 receptor
• Adenylyl Cyclases
• SB 271046

Topics

• Adenylyl Cyclases (metabolism)
• Administration, Oral
• Animals
• Binding, Competitive
• Brain (drug effects, metabolism)
• Cognition (drug effects)
• Disease Models, Animal
• Electric Stimulation
• HeLa Cells
• Humans
• Male
• Radioligand Assay
• Rats
• Rats, Sprague-Dawley
• Receptors, Serotonin (drug effects, metabolism)
• Recombinant Proteins (antagonists & inhibitors, metabolism)
• Seizures (prevention & control)
• Serotonin Antagonists (pharmacology, therapeutic use)
• Sulfonamides (pharmacology, therapeutic use)
• Thiophenes (pharmacology, therapeutic use)
• Transfection