IN-VITRO AND IN-VIVO PROFILE OF SB-206553, A POTENT 5-HT2C 5-HT2B RECEPTOR ANTAGONIST WITH ANXIOLYTIC-LIKE PROPERTIES/

1 SE 206553 carbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole) display s a high affinity (pK(I) 7.9) for the cloned human 5-HT2C receptor exp ressed in HEK 293 cells and the 5-HT2B receptor (pA(2) 8.9) as measure d in the rat stomach fundus preparation. SE 206553 has low affinity fo r 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-stimulate d 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 rec eptor function in vivo. 4 At similar doses (2-20 mg kg(-1), p.o.) SB 2 06553 increased total interaction scores in a rat social interaction t est 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 marm oset conflict model of anxiety at somewhat higher doses (15 and 20 mg kg(-1), p.o.) but also reduced unsuppressed responding. 6 These result s suggest that SB 206553 is a potent mixed 5-HT2C/5-HT2B receptor anta gonist with selectivity over the 5-HT2A and all other sites studied an d possesses anxiolytic-like properties.