Serotonin 5-HT2 receptor, dopamine D-2 receptor, and alpha(1) adrenoceptor antagonists. Conformationally flexible analogues of the atypical antipsychotic sertindole

• Published in: Journal of medicinal chemistry Vol. 39; no. 19; pp. 3723 - 3738
• Main Authors: Andersen, K, Liljefors, T, Hyttel, J, Perregaard, J
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 13.09.1996
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; ACTIVATION; INHIBITION; INVIVO; PHARMACOLOGY; RATS; SITE-DIRECTED MUTAGENESIS; BINDING; SELECTIVITY; DERIVATIVES; INTERACTION-MODEL
• ISSN: 0022-2623
• DOI: 10.1021/jm960159f

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]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 D-2 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 D-2 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 D-2 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]meth ylamino]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 D-2 versus low affinity for serotonin 5-HT2A receptors and alpha(1) adrenoceptors.