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

SB-243213 (5-methyl-1-[[-2-[(2-methyl-3-pyridyl)oxyl-5-pyridyl]carbamoyl]-6 -trifluoromethylindoline hydrochloride) is a new, selective 5-hydroxytrypta mine (5-HT)(2C) receptor inverse agonist. SB-243213 has high affinity for t he human 5-HT2C receptor (pK(i) 9.37) and greater than a 100-fold selectivi ty over a wide range of neurotransmitter receptors, enzymes and ion channel s. 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-2432 13 was a potent inhibitor of central 5-HT2C receptor-mediated function in r ats, blocking meta-chlorophenylpiperazine-induced hypolocomotion with an ID 50 of 1.1 mg/kg p.o. and a long duration of action (>8 h). In rats, SB-2432 13 exhibited anxiolytic-like activity in both the social interaction and Ge ller-Seifter conflict tests. Importantly, unlike diazepam, chronic administ ration of SB-243213 did not result in the development of either tolerance t o the anxiolytic-like effects or withdrawal anxiogenesis. Furthermore, in r odents, SB-243213 did not affect seizure threshold, did not increase body w eight or induce catalepsy, but attenuated the haloperidol-induced catalepsy . SB-243213 did not affect amphetamine-, MK-801- or phencyclidine-induced h yperactivity. In conclusion, SB-243213 may possess an improved anxiolytic p rofile compared to benzodiazepines. SB-243213 also modulates dopaminergic t ransmission, lacks pro-psychotic properties and may have utility in the tre atment of schizophrenia and motor disorders. (C) 2001 Elsevier Science Ltd. All rights reserved.