WAY100135: a novel, selective antagonist at presynaptic and postsynaptic 5-HT1A receptors

Abstract The novel phenylpiperazine derivative, (±)-WAY100135 (N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpro-pionamide dihydrochloride), is a selective antagonist at both somatodendritic and postsynaptic 5-HT 1A receptors. The IC 50 of (±)-WAY100135 at the rat hippocampal 5-HT 1A receptor was 34 nM, whereas its IC 50 at a range of other receptor sites was > 2 μM. Up to a dose of 2.5 mg/kg i.v. (±)-WAY100135 induced a maximum 30% inhibition of raphe neuronal firing and (at 0.5 mg/kg i.v.) antagonised the inhibition of firing induced by 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) in anaesthetised rats. (±)-WAY100135 antagonisedd the action of 5-carboxamidoiodotryptamine in the guinea-pig ileum, with a pA 2 of 7.2. (±)-WAY100135 had no agonist-like behavioural effects but antagonised the behavioural syndrome and hypothermia induced by 8-OH-DPAT in the rat and mouse, respectively. The interaction of (±)-WAY100135 with the 5-HT 1A receptor was stereoselective; the (+)-enantiomer being markedly more active in binding, functional and behavioural studies. These data indicate that (±)-WAY100135 is the first highly selective antagonist at both somatodendritic and postsynaptic 5-HT 1A receptors.