Selective, centrally acting serotonin 5-HT2 antagonists. 1. 2- and 6-substituted 1-phenyl-3-(4-piperidinyl)-1H-indoles.

A series of 1-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2-imidazolidinones has been synthesized. The 1-position of the indole is substituted with phenyl groups and in the 2- or 6-positions are additional substituents. An analogous series with the imidazolidinone ring opened to corresponding urea derivatives was also prepared. High potency and selectivity for 5-HT2 receptors (as compared with D2 and alpha 1 receptor affinities) were obtained with medium-large substituents such as 6-chloro, 6-methyl, and 6-trifluoromethyl or a 2-methyl substituent. Larger 6-substituents such as isopropyl considerably reduced activity, while the smaller 6-fluoro substituent afforded unselective compounds. Selective 5-HT2 antagonists were found by combining 6-substitution with both unsubstituted 1-phenyl and substituted 1-phenyl groups (2-F, 4-F, 4-Cl). However, 3-substitution of the phenyl group markedly reduced 5-HT2 receptor affinity, especially with a 3-trifluoromethyl substituent. Introduction of a 3-(2-propyl) substituent in the imidazolidinone ring reduced binding to alpha 1 adrenoceptors with a factor of 3-8. Practically no influence on 5-HT2 and D2 receptor affinities were found by the presence of this substituent compared to the 3-unsubstituted derivatives. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and they had a long duration of action (> 24 h). Especially urea derivatives were found to be considerably more potent at 24 h than at 2 h after subcutaneous administration. Some of the compounds potently inhibited isolation-induced aggression in mice, an effect which, however, did not correlate to 5-HT2 receptor-mediated activities. On the basis of these structure-activity studies 1-[2-[4-[6-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1- piperidinyl]ethyl]-3-(2-propyl)-2-imidazolidinone (Lu 26-042, compound 4c) was selected for further pharmacological and toxicological investigations.