In vitro and in vivo profile of SB 206553, a potent 5‐HT2C/5‐HT2B receptor antagonist with anxiolytic‐like properties

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Abstract
1 SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole) displays a high affinity (pK1 7.9) for the cloned human 5-HT2C receptor expressed in HEK 293 cells and the 5-HT2B receptor (pA2 8.9) as measured in the rat stomach fundus preparation. SB 206553 has low affinity for cloned human 5-HT2A receptors expressed in HEK 293 cells (pK1 5.8) and (pK1 2C receptor (pKB 9.0). 3 The compound potently (ID50 5.5 mg kg−1, p.o., 0.27 mg kg−1, i.v.) inhibited the hypolocomotor response to m-chlorophenylpiperazine (mCPP), a putative model of 5-HT2C/5-HT2B receptor function in vivo. 4 At similar doses (2–20 mg kg−1, p.o.) SB 206553 increased total interaction scores in a rat social interaction test and increased punished responding in a rat Geller-Seifter conflict test. These effects are consistent with the possession of anxiolytic properties. 5 SB 206553 also increased suppressed responding in a marmoset conflict model of anxiety at somewhat higher doses (15 and 20 mg kg−1, p.o.) but also reduced unsuppressed responding. 6 These results suggest that SB 206553 is a potent mixed 5-HT2C/5-HT2B receptor antagonist with selectivity over the 5-HT2A and all other sites studied and possesses anxiolytic-like properties.

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