title: 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.affiliation: Department of Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow Essex, CM19 5AW, UK. martyn_wood-1@sbphrd.com
authors.forename: M D
authors.initials: MD
authors.lastname: Wood
authors.forename: C
authors.initials: C
authors.lastname: Reavill
authors.forename: B
authors.initials: B
authors.lastname: Trail
authors.forename: A
authors.initials: A
authors.lastname: Wilson
authors.forename: T
authors.initials: T
authors.lastname: Stean
authors.forename: G A
authors.initials: GA
authors.lastname: Kennett
authors.forename: S
authors.initials: S
authors.lastname: Lightowler
authors.forename: T P
authors.initials: TP
authors.lastname: Blackburn
authors.forename: D
authors.initials: D
authors.lastname: Thomas
authors.forename: T L
authors.initials: TL
authors.lastname: Gager
authors.forename: G
authors.initials: G
authors.lastname: Riley
authors.forename: V
authors.initials: V
authors.lastname: Holland
authors.forename: S M
authors.initials: SM
authors.lastname: Bromidge
authors.forename: I T
authors.initials: IT
authors.lastname: Forbes
authors.forename: D N
authors.initials: DN
authors.lastname: Middlemiss
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000523:psychology; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D003975:Diazepam / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000378:metabolism; D012919:Social Behavior; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000523:psychology
chemical_list: D014151:Anti-Anxiety Agents; D007211:Indoles; D007295:Inositol Phosphates; D011725:Pyridines; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; C406343:SB 243213; D003975:Diazepam