SEROTONIN 5-HT2 RECEPTOR, DOPAMINE D-2 RECEPTOR, AND ALPHA(1) ADRENOCEPTOR ANTAGONISTS - CONFORMATIONALLY FLEXIBLE ANALOGS OF THE ATYPICAL ANTIPSYCHOTIC SERTINDOLE

Conformationally flexible analogues of the atypical antipsychotic sert indole (1-[2-[4-[5-chloro-1(4-fluorophenyl)- ndol-3-yl]-4-piperidinyl] ethyl]-2-imidazolidinone) were synthesized. Replacement of the 4-piper idinyl ring in sertindole by a 2-(methylamino)ethoxy group or a 2-(met hylamino)ethyl group (e.g. 5-chloro-1-(4-fluorophenyl)-1H-indol-3-ylox y]ethyl methylamino]ethyl]-2-imidazolidinone and -3-yl]-ethyl]methylam ino]propyl]-2-imidazolidinone results in binding affinities for seroto nin 5-HT2A and dopamine D-2 receptors, as well as alpha(1) adrenocepto rs, 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 cap ability of the 2-(methylamino)ethoxy group and the 2-(methylamino)ethy l group to replace the 4-piperidinyl ring in sertindole is reflected i n molecular modeling studies using recently published receptor-interac tion models for 5-HT2 and D-2 receptors. Structure-affinity investigat ions concerning the substituents in the indole nucleus and the 2-imida zolidinone ring system in the 2-(methylamino)ethoxy and the 2-(methyla mino)ethyl analogues of sertindole have led to high affinity serotonin 5-HT2A receptor antagonists with selectivity versus dopamine D-2 rece ptors and alpha(1) adrenoceptors (e.g. 1-[2-[[2-[6-chloro-1-(4-fluorop henyl)-1H -yloxy]ethyl]methylamino]-ethyl]-2-imidazolidinone and chlor o-1-(4-fluorophenyl)-1H-indol-3-yl]ethyl]meth ylamino]propyl]-2-imidaz olidinone). 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 chlo ro-1-(4-fluorophenyl)-3-[(4-methylpiperazinyl) ethoxy]-1H-indole, whic h has high affinity for dopamine D-2 versus low affinity for serotonin 5-HT2A receptors and alpha(1) adrenoceptors.