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| Other names | SB221284 |
| Drug class | Serotonin5-HT2C receptorantagonist;Serotonin5-HT2B receptorantagonist |
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| Formula | C16H14F3N3OS |
| Molar mass | 353.36 g·mol−1 |
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SB-221284 is aselectiveserotonin5-HT2C and5-HT2B receptorantagonist which is used inscientific research.[1][2][3]
Itsaffinities (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 serotonin5-HT2A receptor (where it is also an antagonist).[2][4][3][5] The drug has 160- to 250-foldselectivity 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 receptorligand to show 100-fold selectivity over the serotonin 5-HT2A receptor.[6]
SB-221284 has shownanxiolytic-like effects in animals.[1][5][7][8] Conversely, it has been said to be inactive in terms ofantidepressant-like,antiobsessional-like,antipanic-like, andsedative effects.[1][8] It also showed noproconvulsant orhyperphagic effects in animals,phenotypes that are notably observed with serotonin 5-HT2C receptorknockout.[3]
The preferential serotonin 5-HT2C receptor agonistmeta-chlorophenylpiperazine (mCPP) and theserotonin reuptake inhibitorfluoxetine have been found to acutely reducesocial 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-inducedhypolocomotion.[1][5][7][9] Both SB-221284 and the selective serotonin 5-HT2C receptor antagonistSB-242084 have been found to enhance thenucleus accumbensdopamine release andhyperlocomotion induced byNMDA receptor antagonists likephencyclidine (PCP) anddizocilpine (MK-801).[9] Conversely, both drugs had no effect onlocomotor activity or dopamine release in the nucleus accumbens by themselves.[9] However, another study reported that SB-221284 by itself didenhance locomotion.[4]
SB-221284 was first described in thescientific literature by 1996.[10][3] It was researched byGlaxoSmithKline as a possible non-sedating anxiolytic and reached thepreclinical research stage of development.[5][11][12][3] However, it was found to be apotentinhibitor of a number of humancytochrome P450enzymes (particularlyCYP1A2), 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]
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.
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).
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]
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.
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
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.
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.
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].
