In vitro and in vivo profile of SB 206553, a potent 5‐HT2C/5‐HT2Breceptor antagonist with anxiolytic‐like properties

Abstract

SB 206553 (5‐methyl‐1‐(3‐pyridylcarbamoyl)‐1,2,3,5‐tetrahydropyrrolo[2,3‐f]indole) displays a high affinity (pK 1 7.9) for the cloned human 5‐HT 2C receptor expressed in HEK 293 cells and the 5‐HT 2B receptor (pA 2 8.9) as measured in the rat stomach fundus preparation. SB 206553 has low affinity for cloned human 5‐HT 2A receptors expressed in HEK 293 cells (pK 1 5.8) and (pK 1<6) for a wide variety of other neurotransmitter receptors. SB 206553 appears to be a surmountable antagonist of 5‐HT‐stimulated phosphoinositide hydrolysis in HEK 293 cells expressing the human 5‐HT 2C receptor (pK B 9.0). The compound potently (ID 50 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‐HT 2C/5‐HT 2B receptor function in vivo. 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. 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. These results suggest that SB 206553 is a potent mixed 5‐HT 2C/5‐HT 2B receptor antagonist with selectivity over the 5‐HT 2A and all other sites studied and possesses anxiolytic‐like properties.