Serotonin 5-HT2 receptor, dopamine D2 receptor, and alpha 1 adrenoceptor antagonists. Conformationally flexible analogues of the atypical antipsychotic sertindole.

Abstract

Conformationally flexible analogues of the atypical antipsychotic sertindole (1-[2-[4-[5-chloro -1-(4-fluorophenyl)-1H-indol-3-yl]-4-piperidinyl]ethyl]-2-imidazolidi non e) were synthesized. Replacement of the 4-piperidinyl ring in sertindole by a 2-(methylamino)ethoxy group or a 2-(methylamino)ethyl group (e.g. 1-[2-[2-[5-chloro-1-(4-fluorophenyl)-1H -indol-3-yloxy]ethyl-methylamino]ethyl]-2-imidazolidinone and 1-[3-[[2-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl] -ethyl]methylamino]propyl]-2-imidazolidinone results in binding affinities for serotonin 5-HT2A and dopamine D2 receptors, as well as alpha 1 adrenoceptors, which are very similar to those of sertindole. (Methylamino)alkyl groups of other chain lengths, 3-(methylamino)propyloxy groups, and 2-(methylamino)ethylsulfanyl groups do not have such properties. The capability of the 2-(methylamino)ethoxy group and the 2-(methylamino)ethyl group to replace the 4-piperidinyl ring in sertindole is reflected in molecular modeling studies using recently published receptor-interaction models for 5-HT2 and D2 receptors. Structure-affinity investigations concerning the substituents in the indole nucleus and the 2-imidazolidinone ring system in the 2-(methylamino)ethoxy and the 2-(methylamino)ethyl analogues of sertindole have led to high affinity serotonin 5-HT2A receptor antagonists with selectivity versus dopamine D2 receptors and alpha 1 adrenoceptors (e.g. 1-[2-[[2-[6-chloro-1-(4-fluorophenyl) -1H-indol-3-yloxy]ethyl]methylamino]-ethyl]-2-imidazolidinone and 1-[3-[[2-[6-chloro-1-(4-fluorophenyl) -1H-indol-3-yl]ethyl]methylamino]propyl]-2-imidazolidinone). The latter derivative has also high selectivity for 5-HT2A receptors versus serotonin 5-HT2C receptors. Replacement of the basic amino group by nitrogen-containing six-membered rings has led to 5-chloro-1-(4-fluorophenyl)-3-[(4-methylpiperazinyl)-ethoxy]-1H-in dole, which has high affinity for dopamine D2, versus low affinity for serotonin 5-HT2A receptors and alpha 1 adrenoceptors.