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In vitro and in vivo profile of SB 206553, a potent 5‐HT 2C /5‐HT 2B receptor antagonist with anxiolytic‐like properties
Author(s) -
Kennett G.A.,
Wood M.D.,
Bright F.,
Cilia J.,
Piper D.C.,
Gager T.,
Thomas D.,
Baxter G.S.,
Forbes I.T.,
Ham P.,
Blackburn T.P.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15208.x
Subject(s) - receptor , antagonist , anxiolytic , pharmacology , receptor antagonist , 5 ht receptor , hek 293 cells , chemistry , agonist , serotonin , in vivo , medicine , endocrinology , biology , biochemistry , microbiology and biotechnology
1 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. 2 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). 3 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 . 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‐HT 2C /5‐HT 2B receptor antagonist with selectivity over the 5‐HT 2A and all other sites studied and possesses anxiolytic‐like properties.