The Development of 5-HT2 Receptor Antagonists

Binding studies indicate that both serotonin and dopamine receptors are involved in the mechanism of action of neuroleptic drugs (Leysen et al., 1978), and have distinguished between two 5-HT binding sites, labelled with high affinity either by [3H]-serotonin (5-HT1) or by [3H]-spiperone in the frontal cortex (5-HT2) in various brain tissues (Peroutka and Snyder, 1979). Structural modification of these molecules with neuroleptic properties led to the synthesis of a number of quinazolinedione derivatives. These substances prevented formation of gastric ulcers in rats challenged with compound 48/80 (which induces release of both histamine and serotonin from mast cells); these findings indicated inhibition of serotonin activity, since these rats were protected against histamine-induced effects by treatment with antihistaminic drugs (Awouters et al., 1982). The ability of this group of molecules and of a number of known serotonin antagonists to block serotonin-induced contractions was determined on the isolated caudal artery of the rat (Van Nueten et al., 1981). Their activities correlated significantly with their affinities for 5-HT2 receptors, as measured in radioligand binding studies (Leysen et al., 1982). Of these 5-HT2 receptor antagonists, ketanserin (R 41 468; 3-[2-[4-(p-fluorobenzoyl)-piperidino]ethyl]-2,4(1H,3H)-quinazolinedione) emerged as being the most selective for 5-HT2 receptor sites (Leysen et al., 1981; Van Nueten and Vanhoutte, 1981). It inhibited serotonin-induced contraction of isolated blood vessels (Van Nueten et al., 1981).