SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety.

Abstract

SB-243213 (5-methyl-1-[[-2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline hydrochloride) is a new, selective 5-hydroxytryptamine (5-HT)2C receptor inverse agonist. SB-243213 has high affinity for the human 5-HT2C receptor (pK(i) 9.37) and greater than a 100-fold selectivity over a wide range of neurotransmitter receptors, enzymes and ion channels. In in vitro functional studies, SB-243213 acted as an inverse agonist at the human 5-HT2C receptor with a pK(b) of 9.8. In in vivo studies, SB-243213 was a potent inhibitor of central 5-HT2C receptor-mediated function in rats, blocking meta-chlorophenylpiperazine-induced hypolocomotion with an ID50 of 1.1 mg/kg p.o. and a long duration of action (>8 h). In rats, SB-243213 exhibited anxiolytic-like activity in both the social interaction and Geller-Seifter conflict tests. Importantly, unlike diazepam, chronic administration of SB-243213 did not result in the development of either tolerance to the anxiolytic-like effects or withdrawal anxiogenesis. Furthermore, in rodents, SB-243213 did not affect seizure threshold, did not increase body weight or induce catalepsy, but attenuated the haloperidol-induced catalepsy. SB-243213 did not affect amphetamine-, MK-801- or phencyclidine-induced hyperactivity. In conclusion, SB-243213 may possess an improved anxiolytic profile compared to benzodiazepines. SB-243213 also modulates dopaminergic transmission, lacks pro-psychotic properties and may have utility in the treatment of schizophrenia and motor disorders.

• Authors: M D Wood, C Reavill, B Trail, A Wilson, T Stean, G A Kennett, S Lightowler, T P Blackburn, D Thomas, T L Gager, G Riley, V Holland, S M Bromidge, I T Forbes, D N Middlemiss
• Journal: Neuropharmacology (Neuropharmacology) Vol. 41 Issue 2 Pg. 186-99 (Aug 2001) ISSN: 0028-3908 [Print] England
• PMID: 11489455 (Publication Type: Journal Article)

Chemical References

• Anti-Anxiety Agents
• Indoles
• Inositol Phosphates
• Pyridines
• Receptor, Serotonin, 5-HT2C
• Receptors, Serotonin
• SB 243213
• Diazepam

Topics

• Animals
• Anti-Anxiety Agents (adverse effects, pharmacology, therapeutic use)
• Anxiety (drug therapy, psychology)
• Catalepsy (chemically induced, drug therapy)
• Diazepam (adverse effects)
• Dose-Response Relationship, Drug
• Drug Tolerance (physiology)
• Humans
• Indoles (pharmacology, therapeutic use)
• Inositol Phosphates (metabolism)
• Male
• Motor Activity (drug effects, physiology)
• Pyridines (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptor, Serotonin, 5-HT2C
• Receptors, Serotonin (metabolism)
• Social Behavior
• Substance Withdrawal Syndrome (drug therapy, psychology)