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SB-271,046

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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
Clinical data
Pregnancy cat.  ?
Legal status  ?
Identifiers
ATC code  ?
PubChem CID 5312149
IUPHAR ligand 276
ChEMBL CHEMBL431298 N
Chemical data
Formula C20H22ClN3O3S2 
Mol. mass 451.989 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

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]

[edit] References

  1. ^ Bromidge, SM; Brown, AM; Clarke, SE; Dodgson, K; Gager, T; Grassam, HL; Jeffrey, PM; Joiner, GF et al. (1999). "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 42 (2): 202–5. doi:10.1021/jm980532e. PMID 9925723. 
  2. ^ Ahmed, M; Briggs, MA; Bromidge, SM; Buck, T; Campbell, L; Deeks, NJ; Garner, A; Gordon, L et al. (2005). "Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists". Bioorganic & medicinal chemistry letters 15 (21): 4867–71. doi:10.1016/j.bmcl.2005.06.107. PMID 16143522. 
  3. ^ Dawson, LA; Nguyen, HQ; Li, P (2000). "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 130 (1): 23–6. doi:10.1038/sj.bjp.0703288. PMC 1572041. PMID 10780993. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1572041. 
  4. ^ Lacroix, LP; Dawson, LA; Hagan, JJ; Heidbreder, CA (2004). "5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex". Synapse 51 (2): 158–64. doi:10.1002/syn.10288. PMID 14618683. 
  5. ^ Dawson, LA; Nguyen, HQ; Li, P (2001). "The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus". Neuropsychopharmacology 25 (5): 662–8. doi:10.1016/S0893-133X(01)00265-2. PMID 11682249. 
  6. ^ Rogers, DC; Hagan, JJ (2001). "5-HT6 receptor antagonists enhance retention of a water maze task in the rat". Psychopharmacology 158 (2): 114–9. doi:10.1007/s002130100840. PMID 11702084. 
  7. ^ Foley, AG; Murphy, KJ; Hirst, WD; Gallagher, HC; Hagan, JJ; Upton, N; Walsh, FS; Regan, CM (2004). "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 29 (1): 93–100. doi:10.1038/sj.npp.1300332. PMID 14571256. 
  8. ^ Marcos, B; Chuang, TT; Gil-Bea, FJ; Ramirez, MJ (2008). "Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat". British journal of pharmacology 155 (3): 434–40. doi:10.1038/bjp.2008.281. PMC 2567877. PMID 18622410. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2567877. 
  9. ^ Minabe, Y; Shirayama, Y; Hashimoto, K; Routledge, C; Hagan, JJ; Ashby Jr, CR (2004). "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 52 (1): 20–8. doi:10.1002/syn.20002. PMID 14755629. 
  10. ^ De Foubert, G; O'Neill, MJ; Zetterström, TS (2007). "Acute onset by 5-HT(6)-receptor activation on rat brain brain-derived neurotrophic factor and activity-regulated cytoskeletal-associated protein mRNA expression". Neuroscience 147 (3): 778–85. doi:10.1016/j.neuroscience.2007.04.045. PMID 17560041. 
  11. ^ Marcos, B; Aisa, B; Ramírez, MJ (2008). "Functional interaction between 5-HT(6) receptors and hypothalamic-pituitary-adrenal axis: cognitive implications". Neuropharmacology 54 (4): 708–14. doi:10.1016/j.neuropharm.2007.11.019. PMID 18206183. 
  12. ^ Loiseau, F; Dekeyne, A; Millan, MJ (2008). "Pro-cognitive effects of 5-HT6 receptor antagonists in the social recognition procedure in rats: implication of the frontal cortex". Psychopharmacology 196 (1): 93–104. doi:10.1007/s00213-007-0934-5. PMID 17922111. 


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