In recent years, multi-targeting directed ligands have attracted great interest as possible new atypical antipsychotics. Combinations of dopamine and serotonin receptor ligands within single molecules might afford new therapeutic opportunities. Herein, we describe the synthesis of a novel series of 6-hydroxypyridazinone benzisoxazoles and their binding behaviors to different receptors in terms of atypical antipsychotic behaviors. The most potent compound (46) exhibited excellent affinities for certain receptors (D2, Ki = 0.5 ± 0.07 nM; 5-HT1A, Ki = 5.9 ± 0.8 nM; 5-HT2A, Ki = 0.3 ± 0.01 nM; 5-HT6, Ki = 0.5 ± 0.04 nM) and combined with low affinities for the H1, 5-HT2C, and adrenergic α1 receptors. In contrast to risperidone, compound 46 exhibited a high cataleptic threshold; this may be useful in the development of a novel class of drugs treating schizophrenia.
Keywords: 6-Hydroxypyridazinone; Atypical antipsychotics; Multi-receptor-target.
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