title: 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.affiliation: Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, Harlow, Essex, U.K.
authors.forename: G A
authors.initials: GA
authors.lastname: Kennett
authors.forename: M D
authors.initials: MD
authors.lastname: Wood
authors.forename: F
authors.initials: F
authors.lastname: Bright
authors.forename: B
authors.initials: B
authors.lastname: Trail
authors.forename: G
authors.initials: G
authors.lastname: Riley
authors.forename: V
authors.initials: V
authors.lastname: Holland
authors.forename: K Y
authors.initials: KY
authors.lastname: Avenell
authors.forename: T
authors.initials: T
authors.lastname: Stean
authors.forename: N
authors.initials: N
authors.lastname: Upton
authors.forename: S
authors.initials: S
authors.lastname: Bromidge
authors.forename: I T
authors.initials: IT
authors.lastname: Forbes
authors.forename: A M
authors.initials: AM
authors.lastname: Brown
authors.forename: D N
authors.initials: DN
authors.lastname: Middlemiss
authors.forename: T P
authors.initials: TP
authors.lastname: Blackburn
mesh_terms: D000631:Aminopyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000523:psychology; D001921:Brain / Q000378:metabolism*; D003220:Conflict, Psychological; D004597:Electroshock; D005247:Feeding Behavior / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010716:Phosphatidylinositols / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D012919:Social Behavior; D014407:Tumor Cells, Cultured
chemical_list: C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D007211:Indoles; D010716:Phosphatidylinositols; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C015068:1-(3-chlorophenyl)piperazine