SB 242084: A Selective 5‐HT2C Receptor Antagonist

SB 242084 is the most potent and selective 5-HT2C receptor antagonist thus far available. Thus, SB 242084 has high affinity for the cloned human 5-HT2C receptor with a pKi of 9.0, a much lower affinity for the human cloned 5-HT2B (pKi 7.0) and 5-HT2A (pKi 6.8) receptors, and low affinity for other 5-HT, dopamine, and adrenergic receptors. In the 5-HT-stimulated PI hydrolysis model of 5-HT2C receptor function, SB 242084 was found to be a competitive antagonist with a pKB of 9.3. A series of in vivo studies have shown that SB 242084 is a very effective antagonist of behavioral responses mediated by 5-HT2C receptors such as penile erections, and the hypophagic and hypolocomotor effect of mCPP in rats. In addition, this compound has anxiolytic-like properties. Moreover, SB 242084 increases the basal activity of dopaminergic neurons in the VTA and the in vivo DA release in the nucleus accumbens, and it is capable of blocking the inhibitory effects of mCPP and RO 60-0175 on mesolimbic dopaminergic activity. These data are consistent with the evidence that 5-HT2C receptors exert an inhibitory control upon the mesolimbic dopaminergic system. Taken togheter, the available data on SB 242084 might have implication for the possible use of this compound in the treatment of anxiety, depression, and the negative symptoms of schizophrenia.