4 At similar doses (2-20 mg kg-', p.o.) SB 206553 increased total interaction scores in a rat social interaction test and increased punished responding in a rat Geller-Seifter conflict test. These effects are consistent with the possession of anxiolytic properties. 5 SB 206553 also increased suppressed responding in a marmoset conflict model of anxiety at somewhat higher doses (15 and 20 mg kg-', p.o.) but also reduced unsuppressed responding. 6 These results suggest that SB 206553 is a potent mixed 5-HT2c/5-HT2B receptor antagonist with selectivity over the 5-HT2A and all other sites studied and possesses anxiolytic-like properties.

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3 In functional studies on human 5-HT 6 receptors SB-271046 competitively antagonized 5-HTinduced stimulation of adenylyl cyclase activity with a pA 2 of 8.71. 4 SB-271046 produced an increase in seizure threshold over a wide-dose range in the rat maximal electroshock seizure threshold (MEST) test, with a minimum e ective dose of 40.1 mg kg 71 p.o. and maximum e ect at 4 h post-dose. The level of anticonvulsant activity achieved correlated well with the blood concentrations of SB-271046 (EC 50 of 0.16 mM) and brain concentrations of 0.01 ± 0.04 mM at C max . 5 These data, together with the observed anticonvulsant activity of other selective 5-HT 6 receptor antagonists, SB-258510 (10 mg kg 71 , 2 ± 6 h pre-test) and Ro 04-6790 (1 ± 30 mg kg 71 , 1 h pre-test), in the rat MEST test, suggest that the anticonvulsant properties of SB-271046 are likely to be mediated by 5-HT 6 receptors. 6 Overall, these studies demonstrate that SB-271046 is a potent and selective 5-HT 6 receptor antagonist and is orally active in the rat MEST test. SB-271046 represents a valuable tool for evaluating the in vivo central function of 5-HT 6 receptors.

1 Xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine] has been reported to act as a functionally selective muscarinic partial agonist with potential use in the treatment of Alzheimer's disease. This study examined the functional activity of xanomeline at 5-HT 1 and 5-HT 2 receptors in native tissue and/or human cloned receptors. 3, was not attenuated by pirenzepine up to 3 mM and was inhibited by the selective 5-HT 1A antagonist WAY100635 with an apparent pK b of 9.4. These data suggest the agonist e ect of xanomeline in this tissue is, in part, via 5-HT 1A receptors. Similar studies on human cloned receptors con®rmed that xanomeline is an agonist at human cloned 5-HT 1A and 5-HT 1B receptors. 4 In studies using the¯uorescent cytoplasmic Ca 2+ indicator FLUO-3AM, xanomeline induced an increase in cytoplasmic Ca 2+ concentration in SH-SY5Y cells expressing recombinant human 5-HT 2C receptors. Atropine antagonized this response, consistent with mediation via endogenously-expressed muscarinic receptors. In the presence of atropine, xanomeline antagonized 5-HT-induced cytoplasmic changes in Ca 2+ concentration in cells expressing h5-HT 2A , h5-HT 2B and h5-HT 2C receptors with potencies similar to its a nity at these receptors. 5 These studies indicate that xanomeline is a potent agonist at 5-HT 1A and 5-HT 1B receptors and an antagonist at 5-HT 2 receptor subtypes.

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