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The S-isomer of the novel 5-HT3 receptor antagonist RS-42358 ((S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1-H- benzo[de]isoquinolin-1-one, RS-42358-197) disinhibited behaviour in the mouse suppressed by the aversive situation of the light/dark test box. RS-42358-197 was effective at sub-ng/kg dose levels and the efficacy was maintained over a 100 million-fold dose range. In contrast, the R-isomer was ineffective at all doses studied. The S-isomer also disinhibited a suppressed behaviour in social interaction and elevated X-maze tests in the rat and reduced anxiety-related behaviours in a marmoset human threat test. RS-42358-197 prevented the exacerbation of the suppression of behaviour in the mouse light/dark test following withdrawal from treatment with alcohol, nicotine, cocaine and diazepam. Thus, the S-isomer of RS-42358 has a consistent non-sedating anxiolytic profile in rodent and primate models. It is exceptionally potent and a maintained efficacy at high doses distinguishes its actions from many other 5-HT3 receptor antagonists.

Three isoxazole bioisosteres of glutamic acid derived from the specific AMPA receptor agonist ( RS )-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) were synthesized and tested electrophysiologically and in different receptor binding systems. ( RS )-2-Amino-3-(3-hydroxy-5-trifluoromethyl-4-isoxazolyl)propionic acid (trifluoro-AMPA, 8) showed more potent agonist activity (EC 50 2.3 μM) and lower affinity (IC 50 0.08 μM) for AMPA receptors than AMPA itself (EC 50 3.5 μM and IC 50 0.04 μM, respectively). Like AMPA, trifluoro-AMPA ( 8 ) did not bind significantly to N -methyl- d -aspartic acid (NMDA) receptor sites, but trifluoro-AMPA ( 8 ) was more potent as an inhibitor of [ 3 H]kainic acid ([ 3 H]KAIN) binding (IC 50 7.1 μM) than AMPA (IC 50 32 μM). ( RS )-2-Amino-3-(3-chloro-5-methyl-4-isoxazolyl)propionic acid ( 14 ), the 3-chloro analogue of AMPA, and the isomeric compound ( RS )-2-amino-3-(3-chloro-4-methyl-5-isoxazolyl)propionic acid ( 15 ), did not show significant neuroexcitatory effects at or affinities for AMPA, NMDA, or KAIN receptor sites.