FURTHER ASSESSMENT OF THE ANTAGONIST PROPERTIES OF THE NOVEL AND SELECTIVE 5-HT(1A) RECEPTOR LIGANDS (-WAY-100-135 AND SDZ-216-525())

In vitro biochemical and electrophysiological methods were used to ass ess the potential antagonist properties of the novel compounds (+)-WAY 100 135 2-methoxyphenyl)piperazin-1-yl-2-phenylpropanamide dihydrochl oride] and SDZ 216-525 [methyl 2-yl)butyl)-l-piperazinyl)1H-indole-2-c arboxylate] at pre- (i.e. somatodendritic autoreceptors) and postsynap tic 5-HT1A receptors in the rat brain. Both (+)-WAY 100 135 and SDZ 21 6-525 were pure antagonists at postsynaptic 5-HT1A receptors negativel y coupled to adenylate cyclase in rat hippocampal membranes. Competiti ve prevention of the inhibition by the 5-HT1A receptor agonists 8-OH-D PAT [8-hydroxy-2-(di-n-propylamino)tetralin], 5-HT (5-hydroxytryptamin e), S-20499 propylamino)butyl-8-azaspiro(4,5)decane-7,9-dione] and les opitron 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 a nd SDZ 216-525 prevented the negative influence of 5-HT1A receptor ago nists (8-OH-DPAT, flesinoxan or lesopitron) on the nerve impulse flow within dorsal raphe nucleus 5-HT neurones in brain stem slices. At hig h concentrations, both (+)-WAY 100 135 (> 1 muM) and SDZ 216-525 (grea ter-than-or-equal-to 0.1 muM) inhibited the spontaneous cell discharge through different mechanisms. The blockade of alpha1-adrenoceptors by (+)-WAY 100 135 apparently accounted for its inhibitory influence on the firing of 5-HT neurones, whereas 5-HT1A receptor agonist propertie s were responsible for the effect of SDZ 216-525. Although approximate ly 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 t he rat brain.