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

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-HT<INF>2A</INF> and dopamine D<INF>2</INF> receptors, as well as α<INF>1</INF> 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-HT<INF>2</INF> and D<INF>2</INF> 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-HT<INF>2A</INF> receptor antagonists with selectivity versus dopamine D<INF>2</INF> receptors and α<INF>1</INF> 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-HT<INF>2A</INF> receptors versus serotonin 5-HT<INF>2C</INF> 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 D<INF>2,</INF> versus low affinity for serotonin 5-HT<INF>2A</INF> receptors and α<INF>1</INF> adrenoceptors.