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SB-271,046
Systematic (IUPAC) name
5-chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-1-benzothiophene-2-sulfonamide
Identifiers
CAS number  ?
ATC code  ?
PubChem 5312149
Chemical data
Formula C 20H22ClN3O3S2  
Mol. mass 451.989 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes  ?

SB-271,046 is a drug which is used in scientific research. It was one of the first selective 5-HT6 receptor antagonists to be discovered, and was found through high-throughput screening of the SmithKline Beecham Compound Bank using cloned 5-HT6 receptors as a target, with an initial lead compound being developed into SB-271,046 through a structure-activity relationship (SAR) study.[1] SB-271,046 was found to be potent and selective in vitro and had good oral bioavailability in vivo, but had poor penetration across the blood-brain barrier, so further SAR work was then conducted, which led to improved 5-HT6 antagonists such as SB-357,134 and SB-399,885.[2]

SB-271,046 was found to increase levels of the excitatory amino acid neurotransmitters glutamate and aspartate,[3] as well as dopamine and noradrenaline[4] in the frontal cortex and hippocampus of rats,[5] and 5-HT6 antagonists have been shown to produce nootropic effects in a variety of animal studies.[6][7][8] Suggested applications of these drugs include treatment of schizophrenia and other psychiatric disorders.[9][10][11][12]

References

  1. ^ Bromidge SM, Brown AM, Clarke SE, Dodgson K, Gager T, Grassam HL, Jeffrey PM, Joiner GF, King FD, Middlemiss DN, Moss SF, Newman H, Riley G, Routledge C, Wyman P. 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. Journal of Medicinal Chemistry. 1999 Jan 28;42(2):202-5. PMID 9925723
  2. ^ Ahmed M, Briggs MA, Bromidge SM, Buck T, Campbell L, Deeks NJ, Garner A, Gordon L, Hamprecht DW, Holland V, Johnson CN, Medhurst AD, Mitchell DJ, Moss SF, Powles J, Seal JT, Stean TO, Stemp G, Thompson M, Trail B, Upton N, Winborn K, Witty DR. Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists. Bioorganic and Medicinal Chemistry Letters. 2005 Nov 1;15(21):4867-71. PMID 16143522
  3. ^ Dawson LA, Nguyen HQ, Li P. In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate. British Journal of Pharmacology. 2000 May;130(1):23-6. PMID 10780993
  4. ^ Lacroix LP, Dawson LA, Hagan JJ, Heidbreder CA. 5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex. Synapse. 2004 Feb;51(2):158-64. PMID 14618683
  5. ^ Dawson LA, Nguyen HQ, Li P. The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology. 2001 Nov;25(5):662-8. PMID 11682249
  6. ^ Rogers DC, Hagan JJ. 5-HT6 receptor antagonists enhance retention of a water maze task in the rat. Psychopharmacology (Berlin). 2001 Nov;158(2):114-9. PMID 11702084
  7. ^ Foley AG, Murphy KJ, Hirst WD, Gallagher HC, Hagan JJ, Upton N, Walsh FS, Regan CM. The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology. 2004 Jan;29(1):93-100. PMID 14571256
  8. ^ Marcos B, Chuang TT, Gil-Bea FJ, Ramirez MJ. Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat. British Journal of Pharmacology. 2008 Oct;155(3):434-40. PMID 18622410
  9. ^ Minabe Y, Shirayama Y, Hashimoto K, Routledge C, Hagan JJ, Ashby CR Jr. Effect of the acute and chronic administration of the selective 5-HT6 receptor antagonist SB-271046 on the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study. Synapse. 2004 Apr;52(1):20-8. PMID 14755629
  10. ^ de Foubert G, O'Neill MJ, Zetterström TS. Acute onset by 5-HT(6)-receptor activation on rat brain brain-derived neurotrophic factor and activity-regulated cytoskeletal-associated protein mRNA expression. Neuroscience. 2007 Jul 13;147(3):778-85. PMID 17560041
  11. ^ Marcos B, Aisa B, Ramírez MJ. Functional interaction between 5-HT(6) receptors and hypothalamic-pituitary-adrenal axis: cognitive implications. Neuropharmacology. 2008 Mar;54(4):708-14. PMID 18206183
  12. ^ Loiseau F, Dekeyne A, Millan MJ. Pro-cognitive effects of 5-HT6 receptor antagonists in the social recognition procedure in rats: implication of the frontal cortex. Psychopharmacology (Berlin). 2008 Jan;196(1):93-104. PMID 17922111
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