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

Br J Pharmacol. 1996 Feb;117(3):427-434. doi: 10.1111/j.1476-5381.1996.tb15208.x.

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 < 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-HT2C 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.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Callithrix
  • Cell Line
  • Conflict, Psychological
  • Female
  • Humans
  • In Vitro Techniques
  • Indoles / pharmacology*
  • Kidney / drug effects
  • Kidney / metabolism
  • Male
  • Motor Activity / drug effects
  • Phosphatidylinositols / metabolism
  • Piperazines / pharmacology
  • Pyridines / pharmacology*
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin Antagonists / pharmacology*
  • Serotonin Receptor Agonists / pharmacology
  • Social Behavior

Substances

  • Anti-Anxiety Agents
  • Indoles
  • Phosphatidylinositols
  • Piperazines
  • Pyridines
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • SB 206553
  • 1-(3-chlorophenyl)piperazine