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Serotonin 5-HT 2 Receptor, Dopamine D 2 Receptor, and α 1 Adrenoceptor Antagonists. Conformationally Flexible Analogues of the Atypical Antipsychotic Sertindole

1996; American Chemical Society; Volume: 39; Issue: 19 Linguagem: Inglês

10.1021/jm960159f

1520-4804

Kim Andersen, Tommy Liljefors, John Hyttel, Jens Perregaard,

Pharmacological Receptor Mechanisms and Effects

Conformationally flexible analogues of the atypical antipsychotic sertindole (1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-4-piperidinyl]ethyl]-2-imidazolidinone) 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]ethylmethylamino]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 α1 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 α1 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-indole, which has high affinity for dopamine D2, versus low affinity for serotonin 5-HT2A receptors and α1 adrenoceptors.