SB-221284

Pharmaceutical compound From Wikipedia, the free encyclopedia

SB-221284 is a selective serotonin 5-HT_2C and 5-HT_2B receptor antagonist which is used in scientific research.^[1]^[2]^[3]

Other namesSB221284

Drug classSerotonin 5-HT_2C receptor antagonist; Serotonin 5-HT_2B receptor antagonist

CAS Number

196965-14-7

PubChem CID

443389

Quick facts Clinical data, Other names ...

SB-221284
Clinical data

Other names	SB221284
Drug class	Serotonin 5-HT_2C receptor antagonist; Serotonin 5-HT_2B receptor antagonist
Identifiers
IUPAC name 5-methylsulfanyl-N-pyridin-3-yl-6-(trifluoromethyl)-2,3-dihydroindole-1-carboxamide
CAS Number	196965-14-7
PubChem CID	443389
IUPHAR/BPS	191
ChemSpider	391618
KEGG	C11741
ChEBI	CHEBI:8978
ChEMBL	ChEMBL276140
CompTox Dashboard (EPA)	DTXSID50332080
Chemical and physical data
Formula	C₁₆H₁₄F₃N₃OS
Molar mass	353.36 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES CSC1=C(C=C2C(=C1)CCN2C(=O)NC3=CN=CC=C3)C(F)(F)F
InChI InChI=1S/C16H14F3N3OS/c1-24-14-7-10-4-6-22(13(10)8-12(14)16(17,18)19)15(23)21-11-3-2-5-20-9-11/h2-3,5,7-9H,4,6H2,1H3,(H,21,23) Key:OQZOXHCRSXYSPM-UHFFFAOYSA-N

Its affinities (K_i) are 2.2 to 2.5 nM for the serotonin 5-HT_2C receptor, 2.5 to 12.6 nM for the serotonin 5-HT_2B receptor, and 398 to 550 nM for the serotonin 5-HT_2A receptor (where it is also an antagonist).^[2]^[4]^[3]^[5] The drug has 160- to 250-fold selectivity for the serotonin 5-HT_2C receptor over the serotonin 5-HT_2A receptor.^[1]^[4]^[3] It is said to have been the first serotonin 5-HT_2C receptor ligand to show 100-fold selectivity over the serotonin 5-HT_2A 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-HT_2C receptor knockout.^[3]

The preferential serotonin 5-HT_2C 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-HT_2C 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-HT_2C receptor antagonist.^[6]

References

[1]
Lacivita E, Leopoldo M (2006). "Selective agents for serotonin2C (5-HT2C) receptor". Current Topics in Medicinal Chemistry. 6 (18): 1927–1970. 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]
Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, et al. (August 2004). "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. doi:10.1007/s00210-004-0951-4. PMID 15322733.
[3]
Bromidge SM, Dabbs S, Davies DT, Duckworth DM, Forbes IT, Ham P, et al. (May 1998). "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. doi:10.1021/jm970741j. PMID 9572885.
[4]
Bristow LJ, O'Connor D, Watts R, Duxon MS, Hutson PH (April 2000). "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. 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]
Yang Y, An S, Liu Y, Guo XX, Gao L, Wei JF, et al. (2 January 2016). "Novel serotonin receptor 2 (5-HT2R) agonists and antagonists: a patent review (2004-2014)". Expert Opinion on Therapeutic Patents. 26 (1): 89–106. 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]
Blaney FE, Capelli AM, Tedesco G (20 January 2006). "7TM Models in Structure-based Drug Design". In Rognan D (ed.). Methods and Principles in Medicinal Chemistry. Wiley. 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]
Bromidge SM, Dabbs S, Davies DT, Davies S, Duckworth DM, Forbes IT, et al. (March 2000). "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. 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]
Jenck F, Bös M, Wichmann J, Stadler H, Martin JR, Moreau JL (October 1998). "The role of 5-HT2C receptors in affective disorders". Expert Opinion on Investigational Drugs. 7 (10): 1587–1599. 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]
Hutson PH, Barton CL, Jay M, Blurton P, Burkamp F, Clarkson R, et al. (September 2000). "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. doi:10.1016/s0028-3908(00)00089-7. PMID 10974315.
[10]
Steele P (1996). "Meeting Highlights: 7th Symposium on Medicinal Chemistry in Eastern England". Expert Opinion on Investigational Drugs. 5 (6): 787–790. 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]
Griebel G (1997). "Serotonergic drugs in animal models of anxiety: an update" (PDF). Serotonin ID Res. Alert. 2: 251–257.
[12]
Pauli I, Timmers LF, Caceres RA, Soares MB, de Azevedo WF (December 2008). "In silico and in vitro: identifying new drugs". Current Drug Targets. 9 (12): 1054–1061. doi:10.2174/138945008786949397. PMID 19128215. 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].

SB-221284

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