WAY100135 - A NOVEL, SELECTIVE ANTAGONIST AT PRESYNAPTIC AND POSTSYNAPTIC 5-HT(1A) RECEPTORS

The novel phenylpiperazine derivative, (+/-)-WAY100135 methoxyphenyl)p iperazin-1-yl)-2-phenylpropionamide dihydrochloride), is a selective a ntagonist at both somatodendritic and postsynaptic 5-HT1A receptors. T he IC50 Of (+/-)-WAY100135 at the rat hippocampal 5-HT1A receptor was 34 nM, whereas its IC50 at a range of other receptor sites was > 2 muM . 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.) antagonis ed the inhibition of firing induced by 8-OH-DPAT (8-hydroxy-2-(di-n-pr opylamino)tetralin) in anaesthetised rats. (+/-)-WAY100135 antagonised the action of 5-carboxamidoiodotryptamine in the guinea-pig ileum, wi th a pA2 Of 7.2. (+/-)-WAY100135 had no agonist-like behavioural effec ts 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-HT1A receptor was stereoselective; the (+)-enan tiomer being markedly more active in binding, functional and behaviour al studies. These data indicate that (+/-)-WAY100135 is the first high ly selective antagonist at both somatodendritic and postsynaptic 5-HT1 A receptors.