SB-242084, A SELECTIVE AND BRAIN PENETRANT 5-HT2C RECEPTOR ANTAGONIST

SB 242084 has a high affinity (pK(i) 9.0) for the cloned human 5-HT2C receptor and 100- and 158-fold selectivity over the closely related cl oned human 5-HT2B and 5-HT2A subtypes respectively. SB 242084 had over 100-fold selectivity over a range of other 5-HT, dopamine and adrener gic receptors. In studies of 5-HT-stimulated phosphatidylinositol hydr olysis using SH-SY5Y cells stably expressing the cloned human 5-HT2C r eceptor, SE 242084 acted as an antagonist with a pK(b) of 9.3, which c losely resembled its corresponding receptor binding affinity. SE 24208 4 potently inhibited m-chIorophenylpiperazine (mCPP, 7 mgkg i.p. 20 mi n 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. SE 242084 (0.1-1 mg/kg i.p.) exhibited an anxiolytic-like pro file in the rat social interaction test, increasing time spent in soci al interaction, but having no effect on locomotion. SE 242084 (0.1-1 m g/kg i.p.) also markedly increased punished responding in a rat Geller -Seifter conflict test of anxiety, but had no consistent effect on unp unished responding. A large acute dose of SE 242084 (30 mg/kg p.o.) ha d no effect on seizure susceptibility in the rat maximal electroshock seizure threshold test. Also, while SE 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 sug gest that SE 242084 is the first reported selective potent and brain p enetrant 5-HT2C receptor antagonist and has anxiolytic-like activity, but does not possess either proconvulsant or hyperphagic properties wh ich are characteristic of mutant mice lacking the 5-HT2C receptor. (C) 1997 Elsevier Science Ltd.