In vitro biochemical and electrophysiological methods were used to assess the potential antagonist properties of the novel compounds (+)-WAY 100 135 [N-tert-butyl-3,4-(2-methoxyphenyl)piperazin-1-yl-2- phenylpropanamide dihydrochloride] and SDZ 216-525 [methyl 4-(4-(4-(1,1,3-trioxo-2H-1,2-benziosothiazol-2-yl)butyl)- 1-piperazinyl)1H-indole-2-carboxylate] at pre- (i.e. somatodendritic autoreceptors) and postsynaptic 5-HT1A receptors in the rat brain. Both (+)-WAY 100 135 and SDZ 216-525 were pure antagonists at postsynaptic 5-HT1A receptors negatively coupled to adenylate cyclase in rat hippocampal membranes. Competitive prevention of the inhibition by the 5-HT1A receptor agonists 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], 5-HT (5-hydroxytryptamine), S-20499 [(+)-4-(N-(5-methoxychroman-3-yl)-N-propylamino)butyl-8-azaspir o(4,5)decane- 7,9-dione] and lesopitron occurred with a pA2 of 8.7 for (+)-WAY 100 135 and 9.9 for SDZ 216-525. The higher potency of the latter compound was also noted at the level of presynaptic 5-HT1A receptors where both (+)-WAY 100 135 and SDZ 216-525 prevented the negative influence of 5-HT1A receptor agonists (8-OH-DPAT, flesinoxan or lesopitron) on the nerve impulse flow within dorsal raphe nucleus 5-HT neurones in brain stem slices. At high concentrations, both (+)-WAY 100 135 (> 1 microM) and SDZ 216-525 (> or = 0.1 microM) inhibited the spontaneous cell discharge through different mechanisms. The blockade of alpha 1-adrenoceptors by (+)-WAY 100 135 apparently accounted for its inhibitory influence on the firing of 5-HT neurones, whereas 5-HT1A receptor agonist properties were responsible for the effect of SDZ 216-525. Although approximately 10 times less potent than SDZ 216-525, (+)-WAY 100 135 is therefore a pure antagonist at both pre- and postsynaptic 5-HT1A receptors in the rat brain.