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

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.

• Authors: G A Kennett, M D Wood, F Bright, B Trail, G Riley, V Holland, K Y Avenell, T Stean, N Upton, S Bromidge, I T Forbes, A M Brown, D N Middlemiss, T P Blackburn
• Journal: Neuropharmacology (Neuropharmacology) Vol. 36 Issue 4-5 Pg. 609-20 ( 1997) ISSN: 0028-3908 [Print] England
• PMID: 9225286 (Publication Type: Journal Article)

Chemical References

• 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

Topics

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