ABSTRACT
As part of an on-going effort to investigate the chemical space requirements for D(2)/5-HT(2A) receptor antagonists as atypical antipsychotics, new 1-aminoindanes were synthesized. The replacement of the heterocycle (oxindole) in ziprasidone with a carbocycle (indane) was well tolerated and was found to retain binding affinities for dopamine D(2), serotonin 5-HT(2A), and serotonin 5-HT(1A). Such compounds hold promise as a new chemical motif with atypical antipsychotic properties for the treatment of schizophrenia and related disorders.
Subject(s)
Antipsychotic Agents/pharmacology , Indans/pharmacology , Antipsychotic Agents/chemistry , Antipsychotic Agents/metabolism , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/drug effects , Humans , Indans/chemistry , Indans/metabolism , Molecular Structure , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Receptors, Dopamine D2/metabolismABSTRACT
Several new, potent dopamine subtype 2 (DA D(2)) active compounds with serotonin subtype 2A (5-HT(2A)) pharmacology are presented. 8-Substituted 3,4-dihydroquinolinones, tetrahydroquinolines, and N-acyl tetrahydroquinolines were evaluated in primary assays. Subtle changes on this novel scaffold translated to large changes in potency and selectivity in vitro. These compounds show promise as novel atypical antipsychotics for the treatment of schizophrenia.
