5-Chloro-<i>N</i>-(4-methoxy-3-piperazin-1-yl- phenyl)-3-methyl-2-benzothiophenesulfon- amide (SB-271046):  A Potent, Selective, and Orally Bioavailable 5-HT<sub>6</sub> Receptor Antagonist

Bromidge, Steven M.; Brown, Anthony M.; Clarke, Stephen E.; Dodgson, Kathy; Gager, Tracey; Grassam, Helen L.; Jeffrey, Phil; Joiner, Graham F.; King, Frank D.; Middlemiss, Derek N.; Moss, Stephen F.; Newman, Helen; Riley, Graham J.; Routledge, Carol; Wyman, Paul

doi:10.1021/jm980532e

Cited by 164 publications

(104 citation statements)

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“…SB271046 (Bromidge et al, 1999) and Ro046790 were the first 5-HT 6 antagonists to be evaluated for their behavioral effects, and both compounds improved retention in a Morris water maze task in rats, suggesting an improvement of spatial memory (Rogers and Hagan, 2001;Woolley et al, 2001). Ro046790 enhanced nonspatial working memory in an object recognition task (ORT) (Woolley et al, 2003), increased consolidation in an autoshaping task, and reversed scopolamine-induced deficits in both an autoshaping and a passive avoidance task (Bos et al, 2001;Meneses, 2001).…”

Section: Introductionmentioning

confidence: 99%

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

Lieben

Blokland

Şık

et al. 2005

Neuropsychopharmacol

135

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Antagonists at serotonin type 6 (5-HT 6 ) receptors show activity in models of learning and memory. Although the underlying mechanism(s) are not well understood, these effects may involve an increase in acetylcholine (ACh) levels. The present study sought to characterize the cognitive-enhancing effects of the 5-HT 6 antagonist Ro4368554 (3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)1H-indole) in a rat object recognition task employing a cholinergic (scopolamine pretreatment) and a serotonergic-(tryptophan (TRP) depletion) deficient model, and compared its pattern of action with that of the acetylcholinesterase inhibitor metrifonate. Initial testing in a time-dependent forgetting task employing a 24-h delay between training and testing showed that metrifonate improved object recognition (at 10 and 30 mg/kg, p.o.), whereas Ro4368554 was inactive. Both, Ro4368554 (3 and 10 mg/kg, intraperitoneally (i.p.)) and metrifonate (10 mg/kg, p.o., respectively) reversed memory deficits induced by scopolamine and TRP depletion (10 mg/kg, i.p., and 3 mg/kg, p.o., respectively). In conclusion, although Ro4368554 did not improve a time-related retention deficit, it reversed a cholinergic and a serotonergic memory deficit, suggesting that both mechanisms may be involved in the facilitation of object memory by Ro4368554 and, possibly, other 5-HT 6 receptor antagonists.

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Section: Introductionmentioning

confidence: 99%

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

Lieben

Blokland

Şık

et al. 2005

Neuropsychopharmacol

135

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“…The first reported 5-HT 6 receptor antagonists were 6 bis-methylamino-pyrimidin-4-yl)-benzene sulfonamide] and 6 bis-methylamino-pyridin-4-yl)-benzene sulfonamide] . These were followed by the potent and highly selective 5-HT 6 antagonists SB-271046 [5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide], SB-357134 [N-(2,5-Dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide] (Bromidge et al, 1999(Bromidge et al, , 2001Routledge et al, 2000;Stean et al, 2002), and the radioligand [ 125 I]SB-258585 [5-iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl-phenyl]benzenesulfonamide] .…”

Section: Introductionmentioning

confidence: 99%

The 5-HT6 Receptor Antagonist SB-271046 Reverses Scopolamine-Disrupted Consolidation of a Passive Avoidance Task and Ameliorates Spatial Task Deficits in Aged Rats

Foley

Murphy

Hirst

et al. 2003

Neuropsychopharmacol

122

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The highly potent and selective 5-HT 6 receptor antagonist SB-271046 [5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide] has previously been demonstrated to improve retention significantly in a spatial water maze paradigm in adult rats. However, SB-271046 did not have any effect on task acquisition. As these apparently contradictory findings may be reconciled by a prime influence of SB-271046 on memory consolidation, the ability of this compound to reverse the discrete temporal action of a cholinergic antagonist in the 6-h period following passive avoidance training was investigated. SB-271046, given orally, by gavage, 30 min prior to training Wistar rats in a step-through, light-dark passive avoidance task, was found to reverse significantly the amnesia produced by administering scopolamine (0.8 mg/kg, intraperitoneal) in the 6-h post-training period. The effect was dose-dependent over a range of 3-20 mg/kg. Further, we investigated the cognition-enhancing effects of chronic SB-271046 administration (10 or 20 mg/kg/day; 40 days) on the acquisition and consolidation of a water maze spatial learning task in a population of 20-month-old Wistar rats with age-related learning deficits. Drug treatment progressively and significantly decreased platform swim angle and escape latencies over the five sequential trials on four consecutive daily sessions compared to vehicle-treated controls. SB-271046 also improved task recall as measured by significant increases in the searching of the target quadrant on post-training days 1 and 3, when the animals would have been substantially drug-free. This significant improvement of task recall suggests SB-271046, in addition to inducing symptomatic cognition-enhancing actions, also attenuates age-related decline in neural function.

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“…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] .…”

Section: Introductionmentioning

confidence: 99%

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

Nirogi

Bandyala

Gangadasari

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of 1-[3-(4-methyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole and 1-[3-(4-ethyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole derivatives were designed and synthesized as 5-HT 6 receptor (5-HT 6 R) ligands. The lead compound 1-[4-methyl-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-1H-indole dihydrochloride (6b), in this series, has shown potent in vitro binding affinity, selectivity, good pharmacokinetics (PK) profile and activity in the animal models of cognition.

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5-Chloro-N-(4-methoxy-3-piperazin-1-yl- phenyl)-3-methyl-2-benzothiophenesulfon- amide (SB-271046): A Potent, Selective, and Orally Bioavailable 5-HT₆ Receptor Antagonist

Cited by 164 publications

References 6 publications

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

The 5-HT6 Receptor Antagonist SB-271046 Reverses Scopolamine-Disrupted Consolidation of a Passive Avoidance Task and Ameliorates Spatial Task Deficits in Aged Rats

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

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5-Chloro-N-(4-methoxy-3-piperazin-1-yl- phenyl)-3-methyl-2-benzothiophenesulfon- amide (SB-271046): A Potent, Selective, and Orally Bioavailable 5-HT6 Receptor Antagonist

Cited by 164 publications

References 6 publications

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

The 5-HT6 Receptor Antagonist SB-271046 Reverses Scopolamine-Disrupted Consolidation of a Passive Avoidance Task and Ameliorates Spatial Task Deficits in Aged Rats

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

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5-Chloro-N-(4-methoxy-3-piperazin-1-yl- phenyl)-3-methyl-2-benzothiophenesulfon- amide (SB-271046): A Potent, Selective, and Orally Bioavailable 5-HT₆ Receptor Antagonist

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