Chemistry:SB-221284

From HandWiki

SB-221284 is a selective serotonin 5-HT2C and 5-HT2B receptor antagonist which is used in scientific research.[1][2][3]

Its affinities (Ki) are 2.2 to 2.5 nM for the serotonin 5-HT2C receptor, 2.5 to 12.6 nM for the serotonin 5-HT2B receptor, and 398 to 550 nM for the serotonin 5-HT2A receptor (where it is also an antagonist).[2][4][3][5] The drug has 160- to 250-fold selectivity for the serotonin 5-HT2C receptor over the serotonin 5-HT2A receptor.[1][4][3] It is said to have been the first serotonin 5-HT2C receptor ligand to show 100-fold selectivity over the serotonin 5-HT2A receptor.[6]

SB-221284 has shown anxiolytic-like effects in animals.[1][5][7][8] Conversely, it has been said to be inactive in terms of antidepressant-like, antiobsessional-like, antipanic-like, and sedative effects.[1][8] It also showed no proconvulsant or hyperphagic effects in animals, phenotypes that are notably observed with serotonin 5-HT2C receptor knockout.[3]

The preferential serotonin 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) and the serotonin reuptake inhibitor fluoxetine have been found to acutely reduce social interaction in rodents.[4] SB-221284 was found to reverse the acute decreases in social interaction produced by mCPP and fluoxetine.[4] The drug has also been found to block mCPP-induced hypolocomotion.[1][5][7][9] Both SB-221284 and the selective serotonin 5-HT2C receptor antagonist SB-242084 have been found to enhance the nucleus accumbens dopamine release and hyperlocomotion induced by NMDA receptor antagonists like phencyclidine (PCP) and dizocilpine (MK-801).[9] Conversely, both drugs had no effect on locomotor activity or dopamine release in the nucleus accumbens by themselves.[9] However, another study reported that SB-221284 by itself did enhance locomotion.[4]

SB-221284 was first described in the scientific literature by 1996.[10][3] It was researched by GlaxoSmithKline as a possible non-sedating anxiolytic and reached the preclinical research stage of development.[5][11][12][3] However, it was found to be a potent inhibitor of a number of human cytochrome P450 enzymes (particularly CYP1A2), which precluded further development of the drug.[1][12][3] Other sources have stated that SB-221284 was not further developed due to "toxicity"[10] and that other drugs were pursued instead as SB-221284 was a "fairly weak" serotonin 5-HT2C receptor antagonist.[6]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Selective agents for serotonin2C (5-HT2C) receptor". Current Topics in Medicinal Chemistry 6 (18): 1927–1970. 2006. doi:10.2174/156802606778522168. PMID 17017967. "In particular, compounds 41 and 42 demonstrated 160- and 600-fold selectivity over 5- HT2A receptor, respectively. [...] Compounds 41-44 were evaluated for binding at 5-HT2B receptor and displayed modest selectivity. Compound 41 was found to have negligible affinity on a total of 57 different binding sites. 41 was also characterized as a competitive antagonist (pKB= 9.8) in the 5-HT-stimulated PI hydrolysis model of h-5-HT2C receptor activation in HEK-293 cells. Compounds 25, 39-43, 47-49 potently blocked the hypoactivity in rats produced by a standard dose of mCPP after oral administration (ID50 values around 1 mg/kg po). [...] Compounds 39, 41, 47, and 48 were further evaluated in two different models of anxiety in the rat (i.e. the Geller-Seifter Conflict Test and the Social Interaction Test) and were found to have significant anxiolytic activity with no evidence of sedative effects at doses (0.2-5 mg/ kg po) similar to those that antagonized mCPP-induced hypolocomotion. [...] The project aimed to the discovery of a selective 5-HT2C receptor antagonist at GSK evolved further [20] starting from compound 41 (SB-221284) and its methoxy analog 47 (Table 2). Compound 41 was found to be a potent inhibitor of a number of human cytochrome P450 enzymes (particularly the CYP1A2 isoform) and, therefore, further development was precluded.". 
  2. ↑ 2.0 2.1 "Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors". Naunyn-Schmiedeberg's Archives of Pharmacology 370 (2): 114–123. August 2004. doi:10.1007/s00210-004-0951-4. PMID 15322733. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: synthesis, quantitative structure-activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines". Journal of Medicinal Chemistry 41 (10): 1598–1612. May 1998. doi:10.1021/jm970741j. PMID 9572885. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Evidence for accelerated desensitisation of 5-HT(2C) receptors following combined treatment with fluoxetine and the 5-HT(1A) receptor antagonist, WAY 100,635, in the rat". Neuropharmacology 39 (7): 1222–1236. April 2000. doi:10.1016/s0028-3908(99)00191-4. PMID 10760364. "SB 221284, an antagonist which has recently been disclosed and which has improved affinity and selectivity for 5-HT2C receptors compared to SB 200646A (Ki =2.5, 12.6 and 398 nM at 5-HT2C, 5-HT2B and 5-HT2A receptors, respectively; Bromidge et al., 1998).". 
  5. ↑ 5.0 5.1 5.2 5.3 "Novel serotonin receptor 2 (5-HT2R) agonists and antagonists: a patent review (2004-2014)". Expert Opinion on Therapeutic Patents 26 (1): 89–106. 2 January 2016. doi:10.1517/13543776.2016.1113257. PMID 26609882. "SmithKline Beecham Pharmaceuticals has developed a number of useful anxiolytic agents targeting the 5-HT2C receptor, since the early 1990s. They revealed a number of bispyridyl ether compounds with selective 5-HT2A/2B/2C receptor antagonist activity (e.g., SB-242084 and SB-221284, compound 16 and 17, respectively, FIGURE 2), which exhibited significant anxiolytic activity and blocked the hypolocomotion in rats, centrally mediated by m-chlorophenylpiperazine (mCPP, compound 8, FIGURE 1), which is a hallucinogen also known as ecstasy with selective 5-HT2A/2C/2B agonist activity, an induce behavioral symptoms of anxiety in both animal models and humans.[29–31]". 
  6. ↑ 6.0 6.1 "7TM Models in Structure-based Drug Design". Methods and Principles in Medicinal Chemistry. Wiley. 20 January 2006. pp. 205–239. doi:10.1002/3527608249.ch11. ISBN 978-3-527-31284-9. "This led to the synthesis of SB-221284 (4) which was the first ligand to show over 100-fold selectivity for 5-HT2C [21]. The compound was still fairly weak as an antagonist so further elaboration was necessary." 
  7. ↑ 7.0 7.1 "Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse agonists: identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent". Journal of Medicinal Chemistry 43 (6): 1123–1134. March 2000. doi:10.1021/jm990388c. PMID 10737744. "Subsequently, we developed a number of selective 5-HT2C/B receptor antagonists, such as 1 (SB206553) and 2 (SB-221284), which block the centrally mediated mCPP-induced hypolocomotion in rats. These compounds also exhibited significant anxiolytic activity in several different animal models, lending strong support to our original hypothesis.4-6". 
  8. ↑ 8.0 8.1 "The role of 5-HT2C receptors in affective disorders". Expert Opinion on Investigational Drugs 7 (10): 1587–1599. October 1998. doi:10.1517/13543784.7.10.1587. PMID 15991903. "In contrast, 5-HT2C receptor antagonists such as SB-200646A or SB-221284 show signs of anxiolytic-like activity in tests for conditioned and phobic-like anxiety in rodents whereas they are inactive in tests indicative of antidepressant, anti-OCD and antipanic activity.". 
  9. ↑ 9.0 9.1 9.2 "Activation of mesolimbic dopamine function by phencyclidine is enhanced by 5-HT(2C/2B) receptor antagonists: neurochemical and behavioural studies". Neuropharmacology 39 (12): 2318–2328. September 2000. doi:10.1016/s0028-3908(00)00089-7. PMID 10974315. 
  10. ↑ 10.0 10.1 "Meeting Highlights: 7th Symposium on Medicinal Chemistry in Eastern England". Expert Opinion on Investigational Drugs 5 (6): 787–790. 1996. doi:10.1517/13543784.5.6.787. ISSN 1354-3784. "The result was the optimised indoline SB-221284 (4), with 140-fold 5-HT2c selectivity, pKi = 8.6, ID50 = 1.5 mg/kg, and a minimum effective dose of 1 mg/kg in the Geller-Seifter test. SB-221284 is no longer in development because of compound-related toxicity problems, but a suitable analogue, not identified, has been located as a replacement.". 
  11. ↑ "Serotonergic drugs in animal models of anxiety: an update.". Serotonin ID Res. Alert 2: 251–257. 1997. http://perso.numericable.fr/griebguy/Pub032.pdf. 
  12. ↑ 12.0 12.1 "In silico and in vitro: identifying new drugs". Current Drug Targets 9 (12): 1054–1061. December 2008. doi:10.2174/138945008786949397. PMID 19128215. https://www.arca.fiocruz.br/handle/icict/10114. "Compound SB 221284 was selected on the basis of its overall biological profile for further evaluation as a potential, novel, nonsedating anxiolytic agent. Unfortunately, these compounds were found to be potent inhibitors of several human cytochrome P450 enzymes which precluded their further development [63].". 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:SB-221284&oldid=4038231"