Characterization of SB‐271046: A potent, selective and orally active 5‐HT₆ receptor antagonist

Abstract

3 In functional studies on human 5-HT 6 receptors SB-271046 competitively antagonized 5-HTinduced 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 range in the rat maximal electroshock seizure threshold (MEST) test, with a minimum e ective dose of 40.1 mg kg 71 p.o. and maximum e ect 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 mM) and brain concentrations of 0.01 ± 0.04 mM at C max . 5 These data, together with the observed anticonvulsant activity of other selective 5-HT 6 receptor antagonists, SB-258510 (10 mg kg 71 , 2 ± 6 h pre-test) and Ro 04-6790 (1 ± 30 mg kg 71 , 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. 6 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.

A Null Mutation of the Serotonin 6 Receptor Alters Acute Responses to Ethanol

“…Some studies indicated that 5-HT 6 R antisense oligonucleotides (Bourson et al, 1995;Sleight et al, 1996) or 5-HT 6 R antagonists (Unsworth and Molinoff, 1994;Sleight et al, 1998;Bentley et al, 1999;Routledge et al, 1999) produced yawning-stretching behaviors that could be blocked by the muscarinic cholinergic antagonist atropine or potentiated by the cholinesterase inhibitor physostigmine. Other studies have implicated Rs in the modulation of cognitive processes (Russell and Dias, 2002).…”

Selective 5-HT6 Receptor Blockade Improves Spatial Recognition Memory and Reverses Age-Related Deficits in Spatial Recognition Memory in the Mouse

“…As SB-271046 failed to modify the retrieval performance when administered prior to the retrieval session, such an effect is specific to acquisition and consolidation. On the basis of pharmacokinetic considerations (Routledge et al, 2000), we speculate that SB-271046 administered 60 min before the first trial (acquisition) should interfere to a lesser extent with the consolidation processes than when injected just after the first session, and should thus mainly affect the acquisition phase. This hypothesis seems to be supported by the fact that the beneficial effect of 5-HT6R blockade seems more robust on consolidation (Figure 2b) than on acquisition because this latter effect shows a tendency to decrease with time ( Figure 1b).…”

“…administration, the peak concentration of SB-271046 in the blood would be obtained for a much shorter time, and clearance of the antagonist would be more rapid, than after p.o. administration (peak value at 180 min; Routledge et al, 2000). Under this scenario, administration of SB-271046 60 min before the first trial (acquisition) should have a maximal effect on the acquisition process while preserving the consolidation phase.…”

“…The rationale for this study is threefold: (1) spatial recognition memory in the rodent can be likened to human episodic memory, which refers to the recollection of a unique past experience in terms of what happened, and where and when it happened (Tulving, 2001), and alteration of episodic memory is one of the first deficits observed in humans during normal aging and in neurological disorders such as Alzheimer's disease (Backman et al, 2001;Daselaar et al, 2003); (2) though the significance of 5-HT6R in the mouse is debated (Hirst et al, 2003), these receptors have been recently found in this species at high densities within various brain areas, including the cerebral cortex and hippocampus (Bibancos et al, 2007, Svenningsson et al, 2007 that are known to be pivotal in spatial recognition memory (Kesner et al, 1993;McDonald and White, 1993;Thinus-Blanc et al, 1996); and (3) pharmacological modulation of 5-HT6R in the mouse has been recently demonstrated to modify psychopharmacological performance (Svenningsson et al, 2007;Wesolowska and Nikiforuk, 2007). Thus, we first evaluated in young adult mice the effects of selective blockade of 5-HT6R by SB-271046 (Bromidge et al, 1999;Routledge et al, 2000) on acquisition, consolidation, and retrieval of spatial recognition memory in the two-trial place recognition task in the Y-maze (Dellu et al, 1992(Dellu et al, , 2000. Because (1) aging is associated with spatial learning impairment attributed to deficiency of information consolidation in the hippocampus (Barnes, 1979;Friedman et al, 2007;Gallagher et al, 1993), (2) memory consolidation has been associated with changes in 5-HT6R levels (Meneses et al, 2007), and (3) very few studies have evaluated the role of 5-HT6R in spatial memory in aged rodents (Foley et al, 2004;Hirst et al, 2006), we also investigated, in a second set of experiments, the effects of blockade of 5-HT6R on consolidation of spatial recognition memory in adult and aged mice.…”

Synthesis and biological evaluation of novel N1-phenylsulphonyl indole derivatives as potent and selective 5-HT6R ligands for the treatment of cognitive disorders

“…During this decade or so, there was a plenty of chemistry developed around different nuclei including the indole-based ones or even much simpler biphenyl sulfones and sulfonamides [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]34 ( Figure 2). Suven has reported several series of 1-sulfonylindoles bearing the amino group at 3 or 4 or 5 position of the central core [31][32][33] .…”