Serotonin 5-HT2 receptor, dopamine D2 receptor, and alpha 1 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-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.
Andersen
K
K
Research Department, H. Lundbeck A/S, Copenhagen, Denmark.
Liljefors
T
T
Hyttel
J
J
Perregaard
J
J
D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D065127:Dopamine D2 Receptor Antagonists; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry*; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D009584:Nitrogen / Q000737:chemistry; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000317:Adrenergic alpha-Antagonists; D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D007093:Imidazoles; D007211:Indoles; D011942:Receptors, Adrenergic, alpha; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C030374:indole; C066304:sertindole; D009584:Nitrogen