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

1 SE 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole) displays a high affinity (pK(I) 7.9) for the cloned human 5-HT2C receptor expressed in HEK 293 cells and the 5-HT2B receptor (pA(2) 8.9) as measured in the rat stomach fundus preparation. SE 206553 has low affinity for cloned human 5-HT2A receptors expressed in HEK 293 cells pK(I) 5.8) and(pK(I) < 6) for a wide variety of other neurotransmitter receptors. 2 SE 206553 appears to be a surmountable antagonist of 5-HT-stimulated phosphoinositide hydrolysis in HEK 293 cells expressing the human 5-HT2C receptor (pK(B) 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.