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SB-242084

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(Redirected from SB-242,084)
SB-242084
Identifiers
  • 6-chloro-5-methyl-N-{6-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}indoline-1-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H19ClN4O2
Molar mass394.86 g·mol−1
3D model (JSmol)
  • Cc1cc2CCN(c2cc1Cl)C(=O)Nc(cc4)cnc4Oc3cccnc3C
  • InChI=1S/C21H19ClN4O2/c1-13-10-15-7-9-26(18(15)11-17(13)22)21(27)25-16-5-6-20(24-12-16)28-19-4-3-8-23-14(19)2/h3-6,8,10-12H,7,9H2,1-2H3,(H,25,27)
  • Key:GIUZEIJUFOPTMR-UHFFFAOYSA-N

SB-242084 is a selective antagonist of the serotonin 5-HT2C receptor which is used in scientific research.[1]

It has anxiolytic effects-like effects in rodents,[2] and enhances dopamine signalling in the limbic system,[3] as well as having complex effects on the dopamine release produced by cocaine, increasing it in some brain regions[4][5] but reducing it in others.[6][7] In animal studies, SB-242084 produced stimulant-type activity and reinforcing effects, somewhat similar to but much weaker than cocaine or amphetamines.[8][9] It is self-administered by monkeys.[9] It has been found to increase dopamine levels in the striatum in rats and in the nucleus accumbens in monkeys by about 200%.[10]

The drug has been shown to increase the effectiveness of the selective serotonin reuptake inhibitor (SSRI) class of antidepressants in animals, and may also reduce their side effects.[11][12] SSRIs acutely reduce social interaction in rodents, thought to be an anxiogenic response, and this effect can be reversed by SB-242084.[13][14] In addition, SSRIs have been found to acutely induce hypolocomotion, which can be reversed by SB-242084.[13][15][16]

SB-242084 was under development by GlaxoSmithKline for the treatment of anxiety disorders in the late 1990s.[17] However, its development looks to have been abandoned.[17]

See also

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References

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  1. ^ Kennett GA, Wood MD, Bright F, Trail B, Riley G, Holland V, et al. (1997). "SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist". Neuropharmacology. 36 (4–5): 609–20. doi:10.1016/S0028-3908(97)00038-5. PMID 9225286. S2CID 23032157.
  2. ^ Martin JR, Ballard TM, Higgins GA (April 2002). "Influence of the 5-HT2C receptor antagonist, SB-242084, in tests of anxiety". Pharmacology, Biochemistry, and Behavior. 71 (4): 615–625. doi:10.1016/S0091-3057(01)00713-4. PMID 11888553. S2CID 19142495.
  3. ^ Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E (August 1999). "SB 242084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system". Neuropharmacology. 38 (8): 1195–205. doi:10.1016/S0028-3908(99)00047-7. PMID 10462132. S2CID 39658512.
  4. ^ Navailles S, De Deurwaerdère P, Porras G, Spampinato U (February 2004). "In vivo evidence that 5-HT2C receptor antagonist but not agonist modulates cocaine-induced dopamine outflow in the rat nucleus accumbens and striatum". Neuropsychopharmacology. 29 (2): 319–26. doi:10.1038/sj.npp.1300329. PMID 14560323.
  5. ^ Navailles S, Moison D, Ryczko D, Spampinato U (November 2006). "Region-dependent regulation of mesoaccumbens dopamine neurons in vivo by the constitutive activity of central serotonin2C receptors". Journal of Neurochemistry. 99 (4): 1311–9. doi:10.1111/j.1471-4159.2006.04188.x. PMID 17018023. S2CID 43833462.
  6. ^ Navailles S, Moison D, Cunningham KA, Spampinato U (January 2008). "Differential regulation of the mesoaccumbens dopamine circuit by serotonin2C receptors in the ventral tegmental area and the nucleus accumbens: an in vivo microdialysis study with cocaine". Neuropsychopharmacology. 33 (2): 237–46. doi:10.1038/sj.npp.1301414. PMID 17429406.
  7. ^ Leggio GM, Cathala A, Moison D, Cunningham KA, Piazza PV, Spampinato U (February 2009). "Serotonin2C receptors in the medial prefrontal cortex facilitate cocaine-induced dopamine release in the rat nucleus accumbens". Neuropharmacology. 56 (2): 507–13. doi:10.1016/j.neuropharm.2008.10.005. PMC 3130963. PMID 18977370.
  8. ^ Manvich DF, Kimmel HL, Cooper DA, Howell LL (September 2012). "The serotonin 2C receptor antagonist SB 242084 exhibits abuse-related effects typical of stimulants in squirrel monkeys". The Journal of Pharmacology and Experimental Therapeutics. 342 (3): 761–769. doi:10.1124/jpet.112.195156. PMC 3422522. PMID 22685342.
  9. ^ a b Wold EA, Wild CT, Cunningham KA, Zhou J (2019). "Targeting the 5-HT2C Receptor in Biological Context and the Current State of 5-HT2C Receptor Ligand Development". Curr Top Med Chem. 19 (16): 1381–1398. doi:10.2174/1568026619666190709101449. PMC 6761005. PMID 31288724. [...] pretreatment with a selective 5-HT2CR antagonist enhanced self-administration of low doses of cocaine and cocaine-evoked reinstatement of drug-seeking, while the selective 5-HT2CR antagonist SB242084 is self-administered in primates [73–76].
  10. ^ Banks ML, Bauer CT, Blough BE, Rothman RB, Partilla JS, Baumann MH, Negus SS (June 2014). "Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys". Exp Clin Psychopharmacol. 22 (3): 274–284. doi:10.1037/a0036595. PMC 4067459. PMID 24796848. A corollary of this proposition is that antagonists at 5-HT2C receptors may block endogenous serotonergic tone at these receptors and thereby disinhibit mesolimbic DA neurons. In support of this idea, 5-HT2C antagonists including SB 242,084 have been shown to increase firing rates of DA neurons and produce modest but significant (~200%) increases in DA levels in rat striatum and squirrel monkey nucleus accumbens (but not squirrel monkey caudate) (Alex et al. 2005; Di Giovanni et al. 1999; Manvich et al. 2012b).
  11. ^ Cremers TI, Giorgetti M, Bosker FJ, Hogg S, Arnt J, Mørk A, et al. (October 2004). "Inactivation of 5-HT(2C) receptors potentiates consequences of serotonin reuptake blockade". Neuropsychopharmacology. 29 (10): 1782–9. doi:10.1038/sj.npp.1300474. PMID 15138437.
  12. ^ Burghardt NS, Bush DE, McEwen BS, LeDoux JE (November 2007). "Acute selective serotonin reuptake inhibitors increase conditioned fear expression: blockade with a 5-HT(2C) receptor antagonist". Biological Psychiatry. 62 (10): 1111–8. doi:10.1016/j.biopsych.2006.11.023. PMC 2129095. PMID 17524369.
  13. ^ a b Bagdy G, Graf M, Anheuer ZE, Modos EA, Kantor S (December 2001). "Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635". Int J Neuropsychopharmacol. 4 (4): 399–408. doi:10.1017/S1461145701002632. PMID 11806866.
  14. ^ Dekeyne A, Denorme B, Monneyron S, Millan MJ (April 2000). "Citalopram reduces social interaction in rats by activation of serotonin (5-HT)(2C) receptors". Neuropharmacology. 39 (6): 1114–1117. doi:10.1016/s0028-3908(99)00268-3. PMID 10727723.
  15. ^ Yamauchi M, Tatebayashi T, Nagase K, Kojima M, Imanishi T (August 2004). "Chronic treatment with fluvoxamine desensitizes 5-HT2C receptor-mediated hypolocomotion in rats". Pharmacol Biochem Behav. 78 (4): 683–689. doi:10.1016/j.pbb.2004.05.003. PMID 15301922.
  16. ^ Shishkina GT, Iudina AM, Dygalo NN (2006). "[Effects of fluoxetine on locomotor activity: possible involvement of dopamine]". Zh Vyssh Nerv Deiat Im I P Pavlova (in Russian). 56 (4): 523–528. PMID 17025197.
  17. ^ a b "SB 242084". AdisInsight. 26 July 2002. Retrieved 14 January 2025.
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