SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist

Neuropharmacology. Apr-May 1997;36(4-5):609-20. doi: 10.1016/s0028-3908(97)00038-5.

Abstract

SB 242084 has a high affinity (pKi 9.0) for the cloned human 5-HT2C receptor and 100- and 158-fold selectivity over the closely related cloned human 5-HT2B and 5-HT2A subtypes respectively. SB 242084 had over 100-fold selectivity over a range of other 5-HT, dopamine and adrenergic receptors. In studies of 5-HT-stimulated phosphatidylinositol hydrolysis using SH-SY5Y cells stably expressing the cloned human 5-HT2C receptor, SB 242084 acted as an antagonist with a pKb of 9.3, which closely resembled its corresponding receptor binding affinity. SB 242084 potently inhibited m-chlorophenylpiperazine (mCPP, 7 mgkg i.p. 20 min pre-test)-induced hypolocomotion in rats, a model of in vivo central 5-HT2C receptor function, with an ID50 of 0.11 mg/kg i.p., and 2.0 mg/kg p.o. SB 242084 (0.1-1 mg/kg i.p.) exhibited an anxiolytic-like profile in the rat social interaction test, increasing time spent in social interaction, but having no effect on locomotion. SB 242084 (0.1-1 mg/kg i.p.) also markedly increased punished responding in a rat Geller-Seifter conflict test of anxiety, but had no consistent effect on unpunished responding. A large acute dose of SB 242084 (30 mg/kg p.o.) had no effect on seizure susceptibility in the rat maximal electroshock seizure threshold test. Also, while SB 242084 (2 and 6 mg/kg p.o. 1 hr pre-test) antagonized the hypophagic response to mCPP, neither acute nor subchronic administration of the drug, for 5 days at 2 or 6 mg/kg p.o. twice daily, affected food intake or weight gain. The results suggest that SB 242084 is the first reported selective potent and brain penetrant 5-HT2C receptor antagonist and has anxiolytic-like activity, but does not possess either proconvulsant or hyperphagic properties which are characteristic of mutant mice lacking the 5-HT2C receptor.

MeSH terms

  • Aminopyridines / pharmacokinetics
  • Aminopyridines / pharmacology*
  • Animals
  • Anxiety / chemically induced
  • Anxiety / psychology
  • Brain / metabolism*
  • Conflict, Psychological
  • Electroshock
  • Feeding Behavior / drug effects
  • Humans
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Male
  • Motor Activity / drug effects
  • Phosphatidylinositols / metabolism
  • Piperazines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism*
  • Serotonin Antagonists / pharmacokinetics
  • Serotonin Antagonists / pharmacology*
  • Serotonin Receptor Agonists / pharmacology
  • Social Behavior
  • Tumor Cells, Cultured

Substances

  • 6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline
  • Aminopyridines
  • Indoles
  • Phosphatidylinositols
  • Piperazines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • 1-(3-chlorophenyl)piperazine