SB-221284

SB-221284 is a selective serotonin 5-HT_2C and 5-HT_2B receptor antagonist which is used in scientific research.

Its affinities (K_i) are 2.2 to 2.5nM for the serotonin 5-HT_2C receptor, 2.5 to 12.6nM for the serotonin 5-HT_2B receptor, and 398 to 550nM for the serotonin 5-HT_2A receptor (where it is also an antagonist). The drug has 160- to 250-fold selectivity for the serotonin 5-HT_2C receptor over the serotonin 5-HT_2A receptor. 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.

SB-221284 has shown anxiolytic-like effects in animals. Conversely, it has been said to be inactive in terms of antidepressant-like, antiobsessional-like, antipanic-like, and sedative effects. It also showed no proconvulsant or hyperphagic effects in animals, phenotypes that are notably observed with serotonin 5-HT_2C receptor knockout.

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. SB-221284 was found to reverse the acute decreases in social interaction produced by mCPP and fluoxetine. The drug has also been found to block mCPP-induced hypolocomotion. 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). Conversely, both drugs had no effect on locomotor activity or dopamine release in the nucleus accumbens by themselves. However, another study reported that SB-221284 by itself did enhance locomotion.

SB-221284 was first described in the scientific literature by 1996. It was researched by GlaxoSmithKline as a possible non-sedating anxiolytic and reached the preclinical research stage of development. 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. Other sources have stated that SB-221284 was not further developed due to "toxicity" and that other drugs were pursued instead as SB-221284 was a "fairly weak" serotonin 5-HT_2C receptor antagonist.

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